Pyrimidine derivatives as PGE2 receptor modulators

ABSTRACT

The present invention relates to pyrimidine derivatives of formula (I) 
                         
wherein (R 1 ) n , R 3 , R 4a , R 4b , R 5a , R 5b  and Ar 1  are as described in the description and their use in the treatment of cancer by modulating an immune response comprising a reactivation of the immune system in the tumor. The invention further relates to novel benzofurane and benzothiophene derivatives of formula (II) and their use as pharmaceuticals, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as modulators of the prostaglandin 2 receptors EP2 and/or EP4.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a United States Application under 35 U.S.C. 371claiming benefit of PCT Application No. PCT/EP2018/062844, filed on May17, 2018, which claims the benefit of PCT Application No.PCT/EP2017/061989, filed on May 18, 2017.

The present invention relates to pyrimidine derivatives of formula (I)and their use in the treatment of cancer by modulating an immuneresponse comprising a reactivation of the immune system in the tumor.The present invention further relates to novel pyrimidine derivatives offormula (II) and their use as pharmaceuticals. The invention alsoconcerns related aspects including processes for the preparation of thecompounds, pharmaceutical compositions containing one or more compoundsof formula (I)/formula (II), and their use as modulators of the PGE2receptors EP2 (alias PTGER2, alias PGE2 Receptor EP2 Subtype) and/or EP4(alias PTGER4, alias EP4R, alias PGE2 Receptor EP4 Subtype). Thecompounds of formula (I)/formula (II) may especially be used as singleagents or in combination with one or more therapeutic agents and/orchemotherapy and/or radiotherapy and/or immunotherapy in theprevention/prophylaxis or treatment of cancers; in particular theprevention/prophylaxis or treatment of melanoma; lung cancer; bladdercancer; renal carcinomas; gastro-intestinal cancers; endometrial cancer;ovarian cancer; cervical cancer; and neuroblastoma.

Prostaglandin E2 (PGE2) is a bioactive lipid that can elicit a widerange of biological effects associated with inflammation and cancer.PGE2 belongs to the prostanoid family of lipids. Cyclooxygenase (COX) isthe rate-limiting enzyme in the synthesis of biological mediators termedprostanoids, consisting of prostaglandin PGD2, PGE2, PGF2α, prostacyclinPGI2, and thromboxane TXA2. Prostanoids function via activation of seventransmembrane G-protein-coupled receptors (GPCRs), in particular EP1,EP2, EP3, and EP4 are receptors for PGE2. Activation of both EP2 and EP4by PGE2 stimulates adenylate cyclase, resulting in elevation ofcytoplasmic cAMP levels to initiate multiple downstream events via itsprototypical effector Protein kinase A. In addition, PGE2 is also ableto signal via PI3K/AKT and Ras-MAPK/ERK signalling

Cancers figure among the leading causes of death worldwide. Tumors arecomprised of abnormally proliferating malignant cancer cells but also ofa functionally supportive microenvironment. This tumor microenvironmentis comprised of a complex array of cells, extracellular matrixcomponents, and signaling molecules and is established by the alteredcommunication between stromal and tumor cells. As tumors expand in size,they elicit the production of diverse factors that can help the tumor togrow such as angiogenic factors (promoting ingrowth of blood vessels) orthat can help to evade the attack of the host immune response. PGE2 issuch an immuno-modulatory factor produced in tumors.

It is well established that COX2, mainly via PGE2, promotes overallgrowth of tumors and is upregulated and correlates with clinical outcomein a high percentage of common cancers, especially colorectal, gastric,esophageal, pancreatic, breast and ovarian cancer. High COX-2 and PGE2expression levels are associated with neoplastic transformation, cellgrowth, angiogenesis, invasiveness, metastasis and immune evasion.

The finding that COX2 is over-expressed and plays an important role incarcinogenesis in gastrointestinal (GI) cancers including among othersesophagus, gastric and colorectal cancers has led to the fact thatCOX-inhibitors (Coxibs), including Celecoxib, and other nonsteroidalanti-inflammatory drugs (NSAID), including aspirin, are among the moststudied cancer chemopreventive agents in development today (for reviewsee for example Wang R et al, Curr Pharm Des. 2013; 19(1):115-25; GarciaRodriguez L A et al, Recent Results Cancer Res. 2013; 191:67-93, Sahin IH et al, Cancer Lett. 2014 Apr. 10; 345(2):249-57; Drew D A et al, NatRev Cancer 2016, 16:173; Brotons C et al, Am J Cardiovasc Drugs. 2015April; 15(2):113)

In addition to COX2 and PGE2, also EP receptors, especially EP2 and EP4,are aberrantly over-expressed in multiple types of cancers, especiallyin gastro-intestinal (GI) cancers and pancreatic cancer. Furthermore,the over-expression of PGE2 and/or EP2 and/or EP4 correlates withdiseases progression in some cancer types such as oesophageal squamouscell carcinoma (Kuo K T et al, Ann Surg Onc 2009; 16(2), 352-60);squamous cell carcinoma of the lung (Alaa M et al, Int J Oncol 2009,34(3); 805-12); prostate cancer (Miyata Y et al, Urology 2013,81(1):136-42); Badawi A F and Badr M Z Int J Cancer. 2003,103(1):84-90); head and neck squamous cell carcinoma (Gallo 0 et al, HumPathol. 2002, 33(7):708-14).

In accordance to studies performed with Coxibs, in mice, knockout ofeither COX1, COX2, microsomal prostaglandin E synthase 1 (mPTGES1), EP2or EP4 resulted in reduced tumor incidence and progression in differenttumor models. Conversely, overexpression of COX2 or mPTGES1 intransgenic mice resulted in increased tumor incidence and tumor burden(for review see Nakanishi M. and Rosenberg D. W., Seminars inImmunopathology 2013, 35: 123-137; Fischer S M et al Cancer Prev Res(Phila) 2011 November; 4(11):1728-35; Fulton A M et al Cancer Res 2006;66(20); 9794-97).

Several pharmacological studies to inhibit tumor growth and progressionusing EP receptor antagonists or COX2 inhibitors in different tumormodels have been conducted in mice. Among others, EP antagonists and/orCOX2 inhibitors reduced tumor growth and metastasis in experimentalmodels of colorectal cancer (e.g Yang L et al Cancer Res 2006, 66(19),9665-9672; Pozzi A. et al JBC 279(28); 29797-29804), lung carcinomas(Sharma S et al Cancer Res 2005 65(12), 5211-5220), gastro-intestinalcancer (Oshima H et al Gastroenterology 2011, 140(2); 596-607; Fu S L etal world J Gastroenterol 2004, 10(13); 1971-1974), breast cancer (KunduN et al, Breast Cancer Res Treat 117, 2009; 235-242; Ma X et al,Oncolmmunology 2013; Xin X et al Lab Investigation 2012, 1-14; MarkosyanN et al; Breast Cancer Res 2013, 15:R75), prostate cancer (Xu S et al,Cell Biochem Biophys 2014, Terada et al Cancer Res 70(4) 2010;1606-1615), pancreatic cancer (A-Wadei H A et al, PLOS One 2012,7(8):e43376; Funahashi H et al, Cancer Res 2007, 67(15):7068-71). COX2inhibitors were approved for the treatment of familial adenomatouspolyposis (FAP) which is an inherited pre-disposition syndrome forcolorectal cancer, but later retracted due to cardiovascular sideeffects.

Mechanistically, PGE2 signalling is mainly involved in the crosstalkbetween tumor and stromal cells, thereby creating a microenvironmentwhich is favourable for the tumor to grow. In particular, PGE2signalling via EP2 and EP4 can for example (i) suppress the cytotoxicityand cytokine production of natural killer cells, (ii) skew thepolarization of tumor-associated macrophages towards tumor-promoting M2macrophages (see for example Nakanishi Y et al Carcinogenesis 2011,32:1333-39), (iii) regulate the activation, expansion and effectorfunction of both Tregs (regulatory T cells) and MDSC (myeloid derivedsuppressor cells), which are potent immunosuppressive cells thataccumulate in tumors both in patients and in experimental animal models(see for example Sharma S et al, Cancer Res 2005, 5(12):5211-20; Sinha Pet al Cancer Res 2007, 67(9), 4507-4513; Obermajer N et al, Blood 2011,118(20):5498-5505); (iv) down-regulate IFN-γ, TNF-α IL-12 and IL-2expression in immune cells such as natural killer cells, T-cells,dendritic cells and macrophages, impairing the ability of these immunecells to induce tumor cell apoptosis and restrain tumorigenesis (see forexample Bao Y S et al, Int Immunopharmacol. 2011; 11(10):1599-605; Kim JG and Hahn Y S, Immunol Invest. 2000; 29(3):257-69; Demeuere C E et al,Eur J Immunol. 1997; 27(12):3526-31; Mitsuhashi M et al, J Leukoc Biol.2004; 76(2):322-32; Pockaj B A et al, Ann Surg Oncol. 2004;11(3):328-39; (v) suppress activation, IL-2 responsivness, expansion andcytotoxicity of T-cells thereby contributing to local immunsuppresion(see for example Specht C et al, Int J Cancer 200191:705-712); (vi)inhibit maturation of dendritic cells, their ability to present antigensand to produce IL-12, resulting in abortive activation of cytotoxicT-cells (see for example Ahmadi M et al, Cancer Res 2008, 68(18):7250-9;Stolina M et al, J Immunol 2000, 164:361-70); (vii) regulate tumorangiogenesis (formation of new blood vessels for nutrient and oxygensupply) by enhancing endothelial cell motility and survival as well asby increasing the expression of VEGF (vascular endothelial growthfactor) (see for example Zhang Y and Daaka Y, Blood 2011;118(19):5355-64; Jain S et al, Cancer Res. 2008; 68(19):7750-9; Wang andKlein, Molecular Carcinogenesis 2007, 46:912-923; (viii) enhance tumorcell survival (via PI3K/AKT and MAPK signalling). For review see forexample Kalinski P, J Immunol 2012, 188(1), 21-28; Obermajer N et al,Oncoimmunology 1(5), 762-4; Greenhough A et al, carcinogenesis 2009,30(3), 377-86; Wang D and Dubois R N, Gut 2006, 55, 115-122; Harris S Ge al Trends Immunol 2002, 22, 144-150).

Coxibs have been shown to render tumor cells more sensitive to radiationand chemotherapy and several clinical trials have been performed or areongoing combining Coxibs with radio- and/or chemotherapy (for review seee.g Ghosh N et al, Pharmacol Rep. 2010 March-April; 62(2):233-44; DavisT W et al, Am J Clin Oncol. 2003, 26(4):S58-61; see also Higgins J P etal, Cancer Biol Ther 2009, 8:1440-49).

Furthermore, there is some evidence of additive effects and/or synergybetween Coxibs and epidermal growth factor receptor (EGFR) inhibitors(see for example Zhang X et al, Clin Cancer Res. 2005, 11(17):6261-9;Yamaguchi N H et al, J Gastrointest Oncol. 2014, 5(1):57-66); and witharomatase inhibitors (see for example Generali D et al, Br J Cancer.2014; 111(1):46-54; Lustberg M B et all, Clin Breast Cancer. 2011August; 11(4):221-7; Falandry C et al, Breast Cancer Res Treat. 2009August; 116(3):501-8); Chow L W et al, J Steroid Biochem Mol Biol. 2008,111(1-2):13-7).

Moreover, additive/synergistic effects have been seen in different mousetumor models when Aspirin (a COX1/2 inhibitor) was combined with andanti-VEGF antibody (Motz G T et al; Nat Med 2014 20(6):607) and thiscombination is currently under investigation in clinical trials(NCT02659384).

Recently, it has been shown that, if combined, differentimmunotherapeutic approaches can have enhanced anti-tumor efficacy. Dueto the immune-modulatory properties of PGE2, Coxibs have thus also beenused in combination with different immunotherapeutic approaches. Inparticular, additive or even synergistic effects could be observed whenCoxibs were combined with dendritic cell vaccination in a rat gliomamodel and in a mouse mesothelioma or melanoma model (Zhang H et al,Oncol Res. 2013; 20(10):447-55; Veltman J D et al, BMC Cancer. 2010;10:464; Toomey D et all, Vaccine. 2008 Jun. 25; 26(27-28):3540-9); withgranulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse braintumors (Eberstál S et al, Int J Cancer. 2014 Jun. 1; 134(11):2748-53);with interferon gamma (IFN-γ) in brain tumors (Eberstál S et al, CancerImmunol Immunother. 2012, 61(8):1191-9); with dendritic cell vaccinationor with GM-CSF in a mouse breast cancer model (Hahn T et al, Int JCancer. 2006, 118(9):2220-31); and with adenoviral interferon beta(IFN-β) therapy in a mouse mesothelioma model (DeLong P et al, CancerRes. 2003 Nov. 15; 63(22):7845-52). Along these lines, additive or evensynergistic effects of Coxibs and/or EP2 and/or EP4 antagonists can alsobe envisaged with agents acting on cytotoxic T-lymphocyte-associatedprotein 4 (CTLA-4) such as anti-CTLA-4 antibodies; anti-TIM-3antibodies, anti-Lag-3 antibodies; anti-TIGIT antibodies; or, inparticular, with agents acting on programmed cell death protein 1 (PD1),such as anti-PD1 or anti-PDL1 (programmed cell death ligand 1)antibodies (Yongkui Li et al Oncoimmunology 2016, 5(2):e1074374; ZelenayS et al, Cell 2015, 162; 1-14; WO2013/090552, which indicates asynergistic effect of dual EP2 and EP4 blockade in combination withagents acting on PD1).

Adenosine is another endogenous factor with anti-inflammatory propertiesthat is generated through the activity of ectonucleotidases, CD39 andCD73, expressed on various cell types, including regulatory T cells(Treg) (Mandapathil M et al, J Biol Chem. 2010; 285(10):7176-86). Immunecells also respond to Adenosine, because they bear receptors for ADO,which are mainly of the A2a/A2b type (Hoskin D W, et al, Int J Oncol2008, 32:527-535). Signaling via Adenosine receptors and EP2/EP4receptors converges on the cytoplasmic adenylyl cyclase, leading toup-regulation of cAMP. It was shown that Adenosine and PGE2 cooperate inthe suppression of immune responses mediated by regulatory T cells(Mandapathil M et al, J Biol Chem. 2010; 285(36):27571-80; Caiazzo E etal, Biochem Pharmacol. 2016; 112:72-81).

Thus, the present EP2 and/or EP4 antagonists may be useful, alone, or incombination with with one or more therapeutic agents and/or chemotherapyand/or radiotherapy and/or immunotherapy; in particular in combinationwith chemotherapy, radiotherapy, EGFR inhibitors, aromatase inhibitors,anti-angiogenic drugs, adenosine inhibitors, immunotherapy such asespecially PD1 and/or PDL1 blockade, or other targeted therapies; forthe prevention/prophylaxis or treatment of cancers, notably for theprevention/prophylaxis or treatment of skin cancer including melanomaincluding metastatic melanoma; lung cancer including non-small cell lungcancer; bladder cancer including urinary bladder cancer, urothelial cellcarcinoma; renal carcinomas including renal cell carcinoma, metastaticrenal cell carcinoma, metastatic renal clear cell carcinoma;gastro-intestinal cancers including colorectal cancer, metastaticcolorectal cancer, familial adenomatous polyposis (FAP), oesophagealcancer, gastric cancer, gallbladder cancer, cholangiocarcinoma,hepatocellular carcinoma, and pancreatic cancer such as pancreaticadenocarcinoma or pancreatic ductal carcinoma; endometrial cancer;ovarian cancer; cervical cancer; neuroblastoma; prostate cancerincluding castrate-resistant prostate cancer; brain tumors includingbrain metastases, malignant gliomas, glioblastoma multiforme,medulloblastoma, meningiomas; breast cancer including triple negativebreast carcinoma; oral tumors; nasopharyngeal tumors; thoracic cancer;head and neck cancer; leukemias including acute myeloid leukemia, adultT-cell leukemia; carcinomas; adenocarcinomas; thyroid carcinomaincluding papillary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma;osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma; lymphoma includingBurkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiplemyelomas; and virally induced tumors.

In addition, selective or dual EP2 and/or EP4 antagonists may be usefulin several other diseases or disorders responding for example totreatment with COX2 inhibitors, with the advantage that EP2 and/or EP4antagonists should not possess the potential cardiovascular side effectsseen with COX2 inhibitors, which are mainly due to interference withPGI2 and TXA2 synthesis (see for example Boyd M J et al, bioorganic andmedicinal chemistry letters 21, 484, 2011). For example, blockade ofprostaglandin production by COX inhibitors is the treatment of choicefor pain, including especially inflammatory pain and painfulmenstruation. Thus EP2 and/or EP4 and/or dual EP2/EP4 antagonists may beuseful for the treatment of pain, especially inflammatory pain. Evidencefrom EP2 knockout mice suggest that EP2 antagonists can be used for thetreatment of inflammatory hyperalgesia (Reinold H et al, J Clin Invest2005, 115(3):673-9). In addition, EP4 antagonists have beneficial effectin vivo in inflammatory pain models (eg Murase A, Eur J Pharmacol 2008;Clark P, J Pharmacol Exp Ther. 2008; Maubach K A Br J Pharmacol. 2009;Colucci J Bioorg Med Chem Lett. 2010, Boyd M J et al, Bioorg Med ChemLett 2011, Chn Q et al Br J Phramacol 2010, Nakao K et al, J PharmacolExp Ther. 2007 August; 322(2):686-94). Administration of an EP2 incombination with an EP4 antagonist showed significant, but partialinhibition of joint inflammation in mouse collagen-induced arthritismodel (Honda T et al J Exp Med 2006, 203(2):325-35).

EP2 and/or dual EP2/EP4 antagonists may be of use to decrease femalefertility, i.e. they have been shown to prevent pregnancy if used ascontraceptive in macaques (Peluffo M C et al Hum Reprod 2014). EP2knockout mice have decreased fertility, smaller litter sizes and reducedcumulus expansion (Matsumoto et al, Biology of reproduction 2001, 64;1557-65; Hitzaki et al, PNAS 1999, 96(18), 10501-10506; Tilley S L JClin Inves 1999, 103(11):1539-45; Kennedy C R et al, Nat Med 19995(2):217-20).

There is also rationale that EP2 and/or EP4 antagonists may be of use toprevent or treat endometriosis: for example EP2, EP3 and EP4 and COX2are overexpressed in endometriosis cell lines and tissues (e.g. SantulliP et al J Clin Endocrinol Metab 2014, 99(3):881-90); antagonisttreatment was shown to inhibit the adhesion of endometrial cells invitro (Lee J et al Biol Reprod 2013, 88(3):77; Lee J et al Fertil Steril201, 93(8):2498-506); COX2 inhibitors have been shown to reduceendometric lesions in mice via EP2 (Chuang P C et al, Am J Pathol 2010,176(2):850-60); and antagonist treatment has been shown to induceapoptosis of endometric cells in vitro (Banu S K et al, MOI endocrinol2009, 23(8) 1291-305).

Dual EP2/EP4 antagonists, or the combination of a selective EP2antagonists with a selective EP4 antagonist, may be of potential use forautoimmune disorders; e.g. they have been shown to be effective in mousemodel for multiple sclerosis (MS) (Esaki Y et al PNAS 2010,107(27):12233-8; Schiffmann S et al, Biochem Pharmacol. 2014, 87(4):625-35; see also Kofler D M et al J Clin Invest 2014, 124(6):2513-22).Activation of EP2/EP 4 signalling in cells in vitro (Kojima F et alProstaglandins Other Lipid Mediat 2009, 89:26-33) linked dual orselective EP2 and/or EP4 antagonists to the treatment of rheumatoidarthritis. Also, elevated levels of PGE(2) have been reported insynovial fluid and cartilage from patients with osteoarthritis (OA) andit has been shown that PGE2 stimulates matrix degradation inosteoarthitis chondrocytes via the EP4 receptor (Attur M et al, JImmunol. 2008; 181(7):5082-8).

EP4 overexpression is associated with enhanced inflammatory reaction inatherosclerotic plaques of patients (Cipollone F et al, ArtheriosclerThromb Vasc Biol 2005, 25(9); 1925-31), thus the use of EP4 and/or dualEP2/EP4 antagonists may be indicated for plaque stabilization andprevention/prophylaxis of acute ischemic syndromes. In addition, EP4deficiency suppresses early atherosclerosis, by compromising macrophagesurvival (Babaev V R et al, Cell Metab. 2008 December; 8(6):492-501)

EP2 and/or dual EP2/EP4 antagonists may also be useful in the treatmentof pneumonia: intrapulmonary administration of apoptotic cellsdemonstrated that PGE(2) via EP2 accounts for subsequent impairment oflung recruitment of leukocytes and clearance of Streptococcuspneumoniae, as well as enhanced generation of IL-10 in vivo (Medeiros Alet al J Exp Med 2009 206(1):61-8).

EP2 and/or dual EP2/EP4 antagonists may in addition be useful for thetreatment of neurodegenerative diseases (for review see Cimino P J etal, Curr Med Chem. 2008; 15(19):1863-9). EP2 receptor acceleratesprogression of inflammation in a mouse model of amyotrophic lateralsclerosis (ALS) (Liang X et al, Ann Neurol 2008, 64(3):304-14); COX2inhibitors have been shown to be neuroprotective in rodent models ofstroke, Parkinson disease and ALS (for review see Liang X et al J MolNeurosci 2007, 33(1):94-9), decreased neurotoxicity was observed in EP2knockout mice treated with parkinsonian toxican (Jin J et al, JNeuroinflammation 2007, 4:2), PGE2 via EP2 aggravates neurodegenerationin cultured rat cells (Takadera T et al, Life Sci 2006, 78(16):1878-83); Reduced amyloid burden was observed in Alzheimer's diseasemouse model if crossed with EP2 knockout mice (Liang X et al J Neurosci2005, 25(44):10180-7; Keene C D et al, Am J Pathol. 2010,177(1):346-54). EP2 null mice are protected from CD14-dependent/innateimmunity mediated neuronal damage in neurodegenerative disease (Shie F Set al Glia 2005, 52(1):70-7); PGE2 via EP2 increases amyloid precursorprotein (APP) expression in cultured rat microglial cells (Pooler A M etal Neurosci. Lett. 2004, 362(2):127-30). EP2 antagonist limits oxidativedamage from activation of innate immunity (intracranial injection ofLPS) in the brain and could be used for Alzheimer or HIV associateddementia (Montine T J et al, J Neurochem 2002, 83(2):463-70). In anAlzheimer's disease mouse model cognitive function could be improved bygenetic and pharmacological inhibition of EP4 (Hoshino T et al, JNeurochem 2012, 120(5):795-805).

EP2 and/or dual EP2/EP4 antagonists may also be useful to treatautosomal dominant polycystic kidney disease (ADPKD): PGE2 via EP2induces cystogenesis of human renal epithelial cells; and EP2 was foundto be overexpressed in patient samples (Elberg G et al, Am J PhysiolRenal Physiol 2007, 293(5):F1622-32).

EP4 and/or dual EP2/EP4 antagonists may also be useful to treatosteoporosis: PGE2 stimulates bone resorption mainly via EP4 andpartially via EP2 (Suzawa T et all, Endocrinology. 2000 April;141(4):1554-9), EP4 knockout mice show impaired bone resorption (MiyauraC et al, J Biol Chem 2000, 275(26): 19819-23) and an EP4 antagonistsshowed partial inhibition of PGE(2)-stimulated osteoclastogenesis andosteoclastic bone resorption (Tomita M et al, Bone. 2002 January;30(1):159-63).

WO2008/152093 discloses selective EP2 receptor modulators which comprisean indole ring linked to the rest of the molecule in position 3, and apyrimidine moiety which however is not substituted with a directlylinked aromatic substituent. WO2006/044732 discloses pyrimidinecompounds which are modulators of PGD2 claimed to be useful e.g. in thetreatment of allergic diseases; however, for example the exemplifiedcompound CAS 1001913-77-4 has been tested to be inactive on both the EP2and the EP4 receptor in the in vitro assay set out in the experimentalpart below. WO2008/006583 discloses pyrimidin derivatives which areALK-5 inhibitors. WO2006/044732 and WO2008/039882 disclose certainpyrimidine derivatives as protaglandin D2 receptor antagonists.Pyrimidin-2-yl derivatives are disclosed in WO2013/020945,WO2012/127032, WO2011/144742, WO2011/022348, WO2009/105220, Bioorg. Med.Chem 2011, 21(13) 4108-4114 and Bioorg. Med. Chem 2011, 21(1) 66-75.Further compounds which are claimed to be active as anti-cancer agentsare disclosed in WO2006/128129, WO2008/008059 and Bioorg. Med. Chem2013, 21(2), 540-546. WO2012/149528 discloses 2-methyl-pyrimidinederivatives as inhibitors of the inducible form ofPhosphofructose-Kinase, thought to useful in the treatment of cancer bydecreasing tumor growth by reducing the extremely high rate ofglycolysis in cancer cells. WO2018/013840, WO2013/163190 WO2015/058067,and WO2015/058031 disclose certain DNA-PK inhibitors interacting withDNA repair processes. The disclosed compounds are thought to be usefulto sensitize cancer cells by directly modulating cancer cellproliferation, and to enhance the efficacy of both cancer chemotherapyand radiotherapy.

The present invention provides novel pyrimidine derivatives of formula(I)/formula (II) which are modulators of the prostaglandin 2 receptorsEP2 and/or EP4. Certain compounds of the present invention are dualantagonists of both the EP2 and the EP4 receptor. The present compoundsmay, thus, be useful for the prevention/prophylaxis or treatment ofdiseases which respond to the blockage of the EP2 receptors and/or theEP4 receptors such as especially cancers, wherein a particular aspect isthe treatment of cancer by modulating an immune response comprising areactivation of the immune system in the tumor; as well as painincluding especially inflammatory pain and painful menstruation;endometriosis; acute ischemic syndromes in atherosclerotic patients;pneumonia; neurodegenerative diseases including amyotrophic lateralsclerosis, stroke; Parkinson disease, Alzheimer's disease and HIVassociated dementia; autosomal dominant polycystic kidney disease; andto control female fertility.

1) A first aspect of the invention relates to compounds of the formula(I)

for use in the treatment of a cancer, wherein said cancer is treated bymodulating an immune response comprising a reactivation of the immunesystem in the tumor;wherein said cancer is notably a cancer selected from melanoma includingmetastatic melanoma; lung cancer including non-small cell lung cancer;bladder cancer including urinary bladder cancer, urothelial cellcarcinoma; renal carcinomas including renal cell carcinoma, metastaticrenal cell carcinoma, metastatic renal clear cell carcinoma;gastro-intestinal cancers including colorectal cancer, metastaticcolorectal cancer, familial adenomatous polyposis (FAP), oesophagealcancer, gastric cancer, gallbladder cancer, cholangiocarcinoma,hepatocellular carcinoma, and pancreatic cancer such as pancreaticadenocarcinoma or pancreatic ductal carcinoma; endometrial cancer;ovarian cancer; cervical cancer; neuroblastoma; prostate cancerincluding castrate-resistant prostate cancer; brain tumors includingbrain metastases, malignant gliomas, glioblastoma multiforme,medulloblastoma, meningiomas; breast cancer including triple negativebreast carcinoma; oral tumors; nasopharyngeal tumors; thoracic cancer;head and neck cancer; leukemias including acute myeloid leukemia, adultT-cell leukemia; carcinomas; adenocarcinomas; thyroid carcinomaincluding papillary thyroid carcinoma; choriocarcinoma; Ewing's sarcoma;osteosarcoma; rhabdomyosarcoma; Kaposi's sarcoma; lymphoma includingBurkitt's lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiplemyelomas; and virally induced tumors (especially such cancer is selectedfrom melanoma; lung cancer; bladder cancer; renal carcinomas;gastro-intestinal cancers; endometrial cancer; ovarian cancer; cervicalcancer; and neuroblastoma); wherein said compound is optionally used incombination with one or more chemotherapy agents and/or radiotherapyand/or targeted therapy;wherein in compounds of the formula (I):ring (A) in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- to7-membered ring, which ring (A) is fused to the phenyl group, whereinindependently said ring (A) optionally contains one or two heteroatomsindependently selected from nitrogen, oxygen, and sulfur (notably suchfused group is benzofuranyl, benzothiophenyl, benzothiazolyl,benzoisothiazolyl, indolyl, indazolyl, naphthyl, quinolinyl,isoquinolinyl, 2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,1,2,3,4-tetrahydro-quinolinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl);wherein said fragment is optionally substituted with (R¹)_(n); wherein(R¹)_(n) represents one, two, three, or four optional substituents (i.e.said fragment is unsubstituted, or substituted with one, two, three, orfour R¹), wherein said substituents R¹ are independently selected from(C₁₋₃)alkyl (especially methyl), (C₂₋₃)alkenyl (especially vinyl),(C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy (especially methoxy,ethoxy, isopropoxy), halogen (especially fluoro, or chloro),—S—(C₁₋₃)alkyl (especially methylsulfanyl), (C₁₋₃)fluoroalkyl(especially trifluoromethyl), (C₁₋₃)fluoroalkoxy (especiallytrifluoromethoxy, difluoromethoxy), cyano, oxo, —NR^(N7)R^(N8) whereinR^(N7) and R^(N8) independently represent hydrogen or (C₁₋₄)alkyl(especially methyl);R³ represents hydrogen, methyl or trifluoromethyl (especially hydrogen);R^(4a) and R^(4b) independently represent hydrogen, methyl, or R^(4a)and R^(4b) together with the carbon atom to which they are attachedrepresent a cycloprop-1,1-diyl group;R^(5a) and R^(5b) independently represent hydrogen, methyl, or R^(5a)and R^(5b) together with the carbon atom to which they are attachedrepresent a cycloprop-1,1-diyl group;Ar¹ represents

-   -   phenyl, or 5- or 6-membered heteroaryl (notably 5-membered        heteroaryl, especially thiophenyl or thiazolyl); wherein said        phenyl or 5- or 6-membered heteroaryl independently is mono-,        di- or tri-substituted, wherein the substituents are        independently selected from        -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl, isopropyl,            n-butyl, isobutyl, 1-methyl-propan-1-yl, tert.-butyl,            3-methyl-butyl);        -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,            isopropoxy, n-butoxy, isobutoxy);        -   (C₁₋₃)fluoroalkyl, wherein said (C₁₋₃)fluoroalkyl is            optionally substituted with hydroxy (especially            trifluoromethyl, 2,2,2-trifluoro-1-hydroxy-ethyl);        -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,            trifluoromethoxy, 2,2,2-trifluoroethoxy);        -   halogen (especially fluoro, chloro, bromo);        -   cyano;        -   (C₃₋₆)cycloalkyl, wherein said (C₃₋₆)cycloalkyl is            unsubstituted or mono-substituted with amino (especially            cyclopropyl, 1-amino-cyclopropyl);        -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein said            (C₄₋₆)cycloalkyl containing a ring oxygen atom is            unsubstituted or mono-substituted with hydroxy (especially            3-hydroxy-oxetan-3-yl);        -   (C₃₋₆)cycloalkyl-oxy (especially cyclobutyl-oxy,            cyclopentyl-oxy);        -   hydroxy;        -   —X¹—CO—R^(O1), wherein            -   X¹ represents a direct bond, (C₁₋₃)alkylene (especially                —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                —O—(C₁₋₃)alkylene-* (especially —O—CH₂*, —O—CH(CH₃)—*,                —O—C(CH₃)₂—*, —O—CH₂—CH₂—*), —NH—(C₁₋₃)alkylene-*                (especially —NH—CH₂*, —NH—CH(CH₃)—*), —S—CH₂*, —CF₂—,                —CH═CH—, ethen-1,1-diyl, —CH═CH—, —NH—CO—*, —CO—, or                (C₃₋₅)cycloalkylene; wherein the asterisks indicate the                bond that is linked to the —CO—R^(O1) group; and            -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;                -   —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy,                    or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;                -   —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents                    (C₁₋₄)alkyl or (C₁₋₄)alkoxy;                -   —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                    —O—CH₂—CH₂—N(CH₃)₂); or                -   (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;                    [wherein in particular such group —X¹—CO—R^(O1)                    represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅,                    —O—CH₂—COOH, —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH,                    —O—CH₂—CH₂—COOH, —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃,                    —NH—CH(CH₃)—COOH, —CO—NH—SO₂—CH₃,                    —CO—NH—SO₂—C(CH₃)₂, —CO—NH—SO₂-cyclopropyl,                    —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂, —CO—O—CH₂—COOH,                    —CO—O—CH₂—CH₂—N(CH₃)₂, —CO—O—CH₂—CO—N(CH₃)₂,                    —CO—O—CH₂—O—CO—O—C₂H₅, —CO—O—CH₂—O—CO-propyl,                    (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—,                    —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅,                    —CH₂—CH₂—COOH, —CH═CH—COOH, —CH≡CH—CO—O—C₂H₅,                    —CF₂—COOH, —NH—CO—COOH, —CO—COOH,                    1-carboxy-cyclopropan-1-yl];        -   —CO—CH₂—OH;

-   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;        -   hydroxy-(C₁₋₄)alkyl (especially hydroxymethyl,            1-hydroxy-ethyl);        -   dihydroxy-(C₂₋₄)alkyl (especially 1,2-dihydroxyethyl);        -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);        -   (C₁₋₄)alkoxy-(C₂₋₄)alkoxy (especially 2-methoxy-ethoxy);        -   (CH₂)_(r)CO—NR^(N3)R^(N4) wherein r represents the integer 0            or 1; and wherein R^(N3) and R^(N4) independently represent            hydrogen, (C₁₋₄)alkyl, hydroxy-(C₂₋₄)alkyl,            (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy (wherein preferably at            least one of R^(N3) and R^(N4) represents hydrogen; and            wherein particular examples of such group —CO—NR^(N3)R^(N4)            are —CO—NH₂, —CO—NH(CH₃), —CO—NH(C₂H₅), —CH₂—CO—NH₂,            —CO—NH—C₂H₄—OH, —CO—NH—C₂H₄—OCH₃, or —CO—N(CH₃)₂,            —CO—NH-isopropyl, or —CO—NH—OH);        -   —X²—NR^(N1)R^(N2), wherein X² represents —(CH₂)_(m)—,            wherein m represents the integer 0 or 1; or X² represents            —O—CH₂—CH₂—*, wherein the asterisk indicates the bond that            is linked to the —NR^(N1)R^(N2) group; and wherein            -   R^(N1) and R^(N2) independently represent hydrogen,                (C₁₋₄)alkyl, (C₁₋₄)alkoxy-(C₂₋₄)alkyl, (C₃₋₆)cycloalkyl,                or (C₂₋₃)fluoroalkyl;            -   or R^(N1) independently represents hydrogen or                (C₁₋₄)alkyl, and R^(N2) independently represents —CO—H,                —CO—(C₁₋₃)alkyl, —CO—(C₁₋₃)alkylene-OH, or                —CO—O—(C₁₋₃)alkyl;            -   or R^(N1) and R^(N2) together with the nitrogen to which                they are attached form a 4-, 5- or 6-membered saturated                ring optionally containing one ring oxygen or ring                sulfur atom, wherein said ring is unsubstituted, or                mono-substituted with oxo on a ring carbon atom, or                disubstituted with oxo on a ring sulfur atom;            -   (especially such group —X²—NR^(N1)R^(N2) represents                amino, methylamino, ethylamino, propylamino,                amino-methyl, methylamino-methyl, isobutylamino-methyl,                cyclopropylamino-methyl, cyclobutylamino-methyl,                (2-methoxyethyl)amino-methyl,                (2,2,2-trifluoro-ethyl)-amino; or —NH—CO—H,                —N(C₂H₅)—CO—H, —NH—CO—C₂H₅, —NH—CO—CH₂—CH₂—OH,                —NH—CO—O—CH₃, —N(CH₃)—CO—O—CH₃; or pyrrolidin-1-yl,                2-oxo-pyrrolidin-1-yl, 1,1-dioxo-isothiazolidin-2-yl,                morpholin-4-yl, azetidin-1-yl, or piperidin-1-yl; or                2-(dimethylamino)-ethoxy);        -   —NH—CO—NR^(N)R^(N6) wherein R^(N5) and R^(N6) independently            represent hydrogen or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N5) and R^(N6) represents hydrogen; and            wherein particular examples of such group            —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);        -   —SO₂—R^(S1) wherein R^(S1) represents hydroxy, (C₁₋₄)alkyl            (especially methyl), or —NR^(N7)R^(N8) wherein R^(N7) and            R^(N8) independently represent hydrogen or (C₁₋₃)alkyl            (wherein preferably at least one of R^(N7) and R^(N8)            represents hydrogen; and wherein particular examples of such            group —SO₂—R^(S1) are —SO₂—CH₃, —SO₂—NH₂, —SO₂—OH,            —SO₂—NH—CH₃);        -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl (especially            methyl, ethyl, n-propyl, isopropyl, isobutyl),            (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom            (especially cyclobutyl, oxetan-3-yl);        -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1 or 2            (especially q is 0, i.e. HET¹ is linked to Ar¹ by a direct            bond); and wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl),            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or            5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);        -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1            (especially p is 0, i.e. HET is linked to Ar¹ by a direct            bond); and wherein HET represents a 5- or 6-membered            heteroaryl (especially 5-membered heteroaryl selected from            oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,            thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, and            tetrazolyl), wherein said 5- or 6-membered heteroaryl is            unsubstituted, or mono- or di-substituted, wherein the            substituents are independently selected from (C₁₋₄)alkyl            (especially methyl), (C₁₋₄)alkoxy (especially methoxy),            —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl (especially            hydroxymethyl), (C₃₋₅)cycloalkyl optionally containing one            ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or            —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently            represent hydrogen, (C₁₋₃)alkyl (especially methyl), or            hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);            (especially such group —(CH₂)_(p)-HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,            3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,            5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl,            5-methoxy-[1,2,4]oxadiazol-3-yl,            5-amino-[1,2,4]oxadiazol-3-yl,            5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,            5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,            5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,            5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl);

    -   or Ar¹ represents 8- to 10-membered bicyclic heteroaryl (notably        9- or 10-membered bicyclic heteroaryl; especially indazolyl,        benzoimidazolyl, indolyl, benzotriazolyl, benzofuranyl,        benzooxazolyl, quinoxalinyl, isoquinolinyl, quinolinyl,        pyrrolopyridinyl, or imidazopyridinyl); wherein said 8- to        10-membered bicyclic heteroaryl independently is unsubstituted,        mono-, or di-substituted, wherein the substituents are        independently selected from (C₁₋₄)alkyl (especially methyl);        (C₁₋₄)alkoxy (especially methoxy); (C₁₋₃)fluoroalkyl (especially        trifluoromethyl); (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy); halogen; cyano; hydroxy, or        —(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2) represents hydrogen or        (C₁₋₄)alkyl (especially such group —(C₀₋₃)alkylene-COOR^(O2) is        —COOH); (especially such 8- to 10-membered bicyclic heteroaryl,        if unsubstituted, is 1H-benzoimidazol-5-yl, 1H-indol-6-yl,        1H-indol-5-yl, 1H-indol-2-yl, 1H-indazol-5-yl, isoquinolin-7-yl,        quinolin-6-yl; or, if substituted, is 3-carboxy-1H-indol-6-yl,        4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl,        6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl,        5-(methoxycarbonyl)-1H-indol-2-yl,        6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,        3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or        2-carboxy-benzofuran-6-yl);

    -   or Ar¹ represents a group of the structure (Ar-III):

-   -   wherein ring (B) represents a non-aromatic 5- or 6-membered ring        fused to the phenyl group, wherein ring (B) comprises one or two        heteroatoms independently selected from nitrogen and oxygen        (notably such group (Ar-III) is 2,3-dihydro-benzofuranyl,        2,3-dihydro-1H-indolyl, 2,3-dihydro-benzo[1,4]dioxinyl,        2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl,        2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydro-isoindolyl,        2,3-dihydro-benzooxazolyl, 1,2,3,4-tetrahydro-quinazolinyl,        1,2,3,4-tetrahydro-isoquinolinyl, or        1,2,3,4-tetrahydro-phthalazinyl); wherein said ring (B)        independently is unsubstituted, mono-, or di-substituted,        wherein the substituents are independently selected from oxo,        (C₁₋₆)alkyl (especially methyl, ethyl, propyl, butyl, isobutyl)        and —(C₀₋₃)alkylene-COOR^(O3) wherein R^(O3) represents hydrogen        or (C₁₋₃)alkyl (especially such group (Ar-III) is        2-oxo-2,3-dihydro-benzooxazol-6-yl,        3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,        1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,        2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, or        1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl).

In a sub-embodiment, Ar¹ especially represents

-   -   phenyl, or 5- or 6-membered heteroaryl; wherein said phenyl or        5- or 6-membered heteroaryl independently is mono-, di- or        tri-substituted (especially di-substituted),        -   wherein one of said substituents is selected from            (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein said            (C₄₋₆)cycloalkyl containing a ring oxygen atom is            unsubstituted or mono-substituted with hydroxy; hydroxy;

-   -   -    —X¹—CO—R^(O1); 2-hydroxy-3,4-dioxo-cyclobut-1-enyl;            hydroxy-(C₂₋₄)alkoxy; —(CH₂)_(r)CO—NR^(N3)R^(N4);            —NH—CO—NR^(N)R^(N6); SO₂—R^(S1); —(CH₂)_(q)-HET¹;            —(CH₂)_(p)-HET;        -   and the other of said substituents, if present,            independently are selected from (C₁₋₆)alkyl; (C₁₋₄)alkoxy;            (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy; halogen; cyano;            (C₁₋₆)cycloalkyl, wherein said (C₁₋₆)cycloalkyl is            unsubstituted or mono-substituted with amino;            (C₃₋₆)cycloalkyl-oxy; hydroxy; hydroxy-(C₁₋₄)alkyl;            dihydroxy-(C₂₋₄)alkyl; hydroxy-(C₂₋₄)alkoxy;            (C₁₋₄)alkoxy-(C₂₋₄)alkoxy; —X²—NR^(N1)R^(N2); —S—R^(S2);            wherein the above groups and substituents are as defined in            embodiment 1).

    -   or Ar¹ represents 8- to 10-membered bicyclic heteroaryl as        defined in embodiment 1); wherein said 8- to 10-membered        bicyclic heteroaryl independently is unsubstituted, mono-, or        di-substituted, wherein the substituents are independently        selected from (C₁₋₄)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl;        (C₁₋₃)fluoroalkoxy; halogen; cyano; hydroxy, or        —(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2) represents hydrogen or        (C₁₋₄)alkyl;

    -   or Ar¹ represents a group of the structure (Ar-III) as defined        in embodiment 1).

2) A second embodiment relates to compounds according to embodiment 1),wherein R³ represents hydrogen.

3) Another embodiment relates to compounds according to embodiment 1),wherein R³ represents methyl.

4) Another embodiment relates to compounds according to any one ofembodiments 1) to 3), wherein R^(4a) and R^(4b) both represent hydrogen.

5) Another embodiment relates to compounds according to any one ofembodiments 1) to 4), wherein R^(5a) and R^(5b) both represent hydrogen.Particular compounds of formula (I) are compounds wherein R^(4a) andR^(4b) both represent hydrogen; and R^(5a) and R^(5b) both representhydrogen.

6) Another embodiment relates to compounds according to any one ofembodiments 1) to 5), wherein the characteristics defined for thefragment

according to embodiments 8), or 17) to 20) below apply mutatis mutandis.

7) Another embodiment relates to compounds according to any one ofembodiments 1) to 6), wherein the characteristics defined for thesubstituent Ar¹ according to embodiments 8), or 11) to 16) below applymutatis mutandis.

8) A second aspect of the invention relates to compounds of the formula(II)

wherein in compounds of the formula (II)ring (A) in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- to7-membered ring, which ring (A) is fused to the phenyl group, whereinsaid ring (A) optionally contains one or two heteroatoms independentlyselected from nitrogen, oxygen, and sulfur (notably such fused group isbenzofuranyl, benzothiophenyl, benzothiazolyl, benzoisothiazolyl,indolyl, indazolyl, naphthyl, quinolinyl, isoquinolinyl,2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,1,2,3,4-tetrahydro-quinolinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl);wherein said fragment is optionally substituted with (R¹)_(n); wherein(R¹)_(n) represents one, two, three, or four optional substituents (i.e.said fragment is unsubstituted, or substituted with one, two, three, orfour R¹), wherein said substituents R¹ are independently selected from(C₁₋₃)alkyl (especially methyl), (C₂₋₃)alkenyl (especially vinyl),(C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy (especially methoxy,ethoxy, isopropoxy), halogen (especially fluoro, or chloro),—S—(C₁₋₃)alkyl (especially methylsulfanyl), (C₁₋₃)fluoroalkyl(especially trifluoromethyl), (C₁₋₃)fluoroalkoxy (especiallytrifluoromethoxy, difluoromethoxy), cyano, oxo, —NR^(N7)R^(N8) whereinR^(N7) and R^(N8) independently represent hydrogen or (C₁₋₄)alkyl(especially methyl);R³ represents hydrogen, or methyl (especially hydrogen);Ar¹ represents

-   -   a phenyl group of the structure (Ar-I):

-   -   wherein        -   R^(p) represents            -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein                said (C₄₋₆)cycloalkyl containing a ring oxygen atom is                unsubstituted or mono-substituted with hydroxy                (especially 3-hydroxy-oxetan-3-yl);            -   hydroxy;            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂*,                    —NH—CH(CH₃)—*), —S—CH₂*, —CF₂—, —CH═CH—,                    ethen-1,1-diyl, —CH≡CH—, —NH—CO—*, —CO—, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -    -OH;                -    -O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -    —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;                -    —O—CH₂—CO—R^(O4), wherein R^(O4) represents                    hydroxy, or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;                -    —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents                    (C₁₋₄)alkyl or (C₁₋₄)alkoxy;                -    -O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                    —O—CH₂—CH₂—N(CH₃)₂); or                -    (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;                -   [wherein in particular such group —X¹—CO—R^(O1)                    represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅,                    —O—CH₂—COOH, —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH,                    —O—CH₂—CH₂—COOH, —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃,                    —NH—CH(CH₃)—COOH, —CO—NH—SO₂—CH₃,                    —CO—NH—SO₂—C(CH₃)₂, —CO—NH—SO₂-cyclopropyl,                    —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂, —CO—O—CH₂—COOH,                    —CO—O—CH₂—CH₂—N(CH₃)₂, —CO—O—CH₂—CO—N(CH₃)₂,                    —CO—O—CH₂—O—CO—O—C₂H₅, —CO—O—CH₂—O—CO-propyl,                    (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—,                    —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅,                    —CH₂—CH₂—COOH, —CH═CH—COOH, —CH≡CH—CO—O—C₂H₅,                    —CF₂—COOH, —NH—CO—COOH, —CO—COOH,                    1-carboxy-cyclopropan-1-yl];

-   -   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;            -   hydroxy-(C₁₋₄)alkyl (especially hydroxymethyl,                1-hydroxy-ethyl);            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);            -   —(CH₂)_(r)CO—NR^(N3)R^(N4) wherein r represents the                integer 0 or 1; and wherein R^(N3) and R^(N4)                independently represent hydrogen, (C₁₋₄)alkyl,                hydroxy-(C₂₋₄)alkyl, (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or                hydroxy (wherein preferably at least one of R^(N3) and                R^(N4) represents hydrogen; and wherein particular                examples of such group —CO—NR^(N3)R^(N4) are —CO—NH₂,                —CO—NH(CH₃), —CO—NH(C₂H₅), —CH₂—CO—NH₂, —CO—NH—C₂H₄—OH,                —CO—NH—C₂H₄—OCH₃, or —CO—N(CH₃)₂, —CO—NH-isopropyl, or                —CO—NH—OH);            -   —NR^(N1)R^(N2), wherein R^(N1) independently represents                hydrogen or (C₁₋₄)alkyl, and R^(N2) independently                represents —CO—H, —CO—(C₁₋₃)alkyl, or                —CO—(C₁₋₃)alkylene-OH; (especially such group                —(CH₂)_(m)—NR^(N1)R^(N2) represents-NH—CO—H,                —N(C₂H₅)—CO—H, —NH—CO—C₂H₅, or —NH—CO—CH₂—CH₂—OH);            -   —NH—CO—NR^(N)R^(N6) wherein R^(N5) and R^(N6)                independently represent hydrogen or (C₁₋₄)alkyl (wherein                preferably at least one of R^(N5) and R^(N6) represents                hydrogen; and wherein particular examples of such group                —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);            -   —SO₂—R^(S1) wherein R^(S1) represents (C₁₋₄)alkyl                (especially methyl), or —NR^(N7)R^(N8) wherein R^(N7)                and R^(N8) independently represent hydrogen or                (C₁₋₃)alkyl (wherein preferably at least one of R^(N7)                and R^(N8) represents hydrogen; and wherein particular                examples of such group —SO₂—R^(S1) are —SO₂—CH₃,                —SO₂—NH₂, —SO₂—NH—CH₃);            -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1                or 2 (especially q is 0, i.e. HET¹ is linked to Ar¹ by a                direct bond); and wherein HET¹ represents                5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl),                3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing                its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or                5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);            -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1                (especially p is 0, i.e. HET is linked to Ar¹ by a                direct bond); and wherein HET represents a 5-membered                heteroaryl (especially oxazolyl, isoxazolyl,                oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,                imidazolyl, pyrazolyl, triazolyl, or tetrazolyl),                wherein said 5-membered heteroaryl is unsubstituted, or                mono- or di-substituted, wherein the substituents are                independently selected from (C₁₋₄)alkyl (especially                methyl), (C₁₋₄)alkoxy (especially methoxy), —COOH,                hydroxy, hydroxy-(C₁₋₃)alkyl (especially hydroxymethyl),                (C₃₋₅)cycloalkyl optionally containing one ring oxygen                atom (especially cyclopropyl, oxetan-3-yl), or                —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently                represent hydrogen, (C₁₋₃)alkyl (especially methyl), or                hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);                (especially such group —(CH₂)_(p)-HET is                1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,                2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl,                2-amino-oxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl,                5-methylamino-[1,3,4]thiadiazol-2-yl,                5-methoxy-[1,2,4]oxadiazol-3-yl,                5-amino-[1,2,4]oxadiazol-3-yl,                5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,                5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,                5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,                5-methyl-1H-imidazol-4-yl,                2,5-dimethyl-1H-imidazol-4-yl);

        -   R^(m1) represents            -   hydrogen;            -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl,                isopropyl, n-butyl, isobutyl);            -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,                isopropoxy, n-butoxy, isobutoxy);            -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);            -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,                trifluoromethoxy, 2,2,2-trifluoroethoxy);            -   halogen (especially fluoro or chloro);            -   (C₃₋₆)cycloalkyl (especially cyclopropyl);            -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,                cyclobutyl-oxy, cyclopentyl-oxy);            -   hydroxy;            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);            -   —X²—NR^(N1)R^(N2), wherein X² represents a direct bond;                or X² represents —O—CH₂—CH₂—*, wherein the asterisk                indicates the bond that is linked to the —NR^(N1)R^(N2)                group; and wherein R^(N1) and R^(N2) independently                represent hydrogen, (C₁₋₄)alkyl (especially methyl), or                (C₃₋₆)cycloalkyl (especially cyclopropyl); (especially                such group —X²—NR^(N1)R^(N2) represents amino,                methylamino, ethylamino, propylamino; or                2-(dimethylamino)-ethoxy);            -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl                (especially methyl, ethyl, n-propyl, isopropyl,                isobutyl), or (C₃₋₆)cycloalkyl optionally containing one                ring oxygen atom (especially cyclobutyl, oxetan-3-yl);

        -   wherein in a sub-embodiment, R^(m1) especially is different            from hydrogen;

        -   R^(m2) represents hydrogen, methyl, fluoro, or chloro; and

        -   R^(o1) represents hydrogen; or, in case R^(m2) represents            hydrogen, R^(o1) represents hydrogen or fluoro;

    -   or Ar¹ represents a 5-membered heteroaryl group of the structure        (Ar-II):

-   -   wherein        -   Y represents CR⁸ wherein R⁸ represents especially hydrogen,            or halogen (notably fluoro, chloro); or Y represents N;        -   R⁷ represents            -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein                said (C₄₋₆)cycloalkyl containing a ring oxygen atom is                unsubstituted or mono-substituted with hydroxy                (especially 3-hydroxy-oxetan-3-yl);            -   —X¹—CO—R^(O1), wherein            -   X¹ represents a direct bond, (C₁₋₃)alkylene (especially                —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*, —O—CH(CH₃)—*,                —O—C(CH₃)₂—*, —O—CH₂—CH₂—*), —NH—(C₁₋₃)alkylene*                (especially —NH—CH₂*, —NH—CH(CH₃)—*), —S—CH₂*, —CF₂—,                —CH═CH—, —CH≡CH—, —NH—CO—*, —CO—, or                (C₃₋₅)cycloalkylene; wherein the asterisks indicate the                bond that is linked to the —CO—R^(O1) group; and            -   R^(O1) represents                -   —OH;                -   —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -   —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₁₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;                -   —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy,                    or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;                -   —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents                    (C₁₋₄)alkyl or (C₁₋₄)alkoxy;                -   —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                    —O—CH₂—CH₂—N(CH₃)₂); or                -   (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CO—O—CH₂—COOH, —CO—O—CH₂—CH₂—N(CH₃)₂,                —CO—O—CH₂—CO—N(CH₃)₂, —CO—O—CH₂—O—CO—O—C₂H₅,                —CO—O—CH₂—O—CO-propyl,                (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—,                —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH,                —CH═CH—COOH, —CH≡CH—CO—O—C₂H₅, —CF₂—COOH, —NH—CO—COOH,                —CO—COOH, 1-carboxy-cyclopropan-1-yl];

-   -   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;            -   hydroxy-(C₁₋₄)alkyl (especially hydroxymethyl,                1-hydroxy-ethyl);            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);            -   —(CH₂)_(r)CO—NR^(N3)R^(N4) wherein r represents the                integer 0 or 1; and wherein R^(N3) and R^(N4)                independently represent hydrogen, (C₁₋₄)alkyl,                hydroxy-(C₂₋₄)alkyl, (C₁₋₃)alkoxy-(C₂₋₄)alkyl, or                hydroxy (wherein preferably at least one of R^(N3) and                R^(N4) represents hydrogen; and wherein particular                examples of such group —CO—NR^(N3)R^(N4) are —CO—NH₂,                —CO—NH(CH₃), —CO—NH(C₂H₅), —CH₂—CO—NH₂, —CO—NH—C₂H₄—OH,                —CO—NH—C₂H₄—OCH₃, or —CO—N(CH₃)₂, —CO—NH-isopropyl, or                —CO—NH—OH);            -   —NR^(N1)R^(N2), wherein R^(N1) independently represents                hydrogen or (C₁₋₄)alkyl, and R^(N2) independently                represents —CO—H, —CO—(C₁₋₃)alkyl, or                —CO—(C₁₋₃)alkylene-OH; (especially such group                —(CH₂)_(m)—NR^(N1)R^(N2) represents-NH—CO—H,                —N(C₂H₅)—CO—H, —NH—CO—C₂H₅, or —NH—CO—CH₂—CH₂—OH);            -   —NH—CO—NR^(N)R^(N6) wherein R^(N5) and R^(N6)                independently represent hydrogen or (C₁₋₄)alkyl (wherein                preferably at least one of R^(N5) and R^(N6) represents                hydrogen; and wherein particular examples of such group                —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);            -   —SO₂—R^(S1) wherein R^(S1) represents (C₁₋₄)alkyl                (especially methyl), or —NR^(N7)R^(N8) wherein R^(N7)                and R^(N8) independently represent hydrogen or                (C₁₋₃)alkyl (wherein preferably at least one of R^(N7)                and R^(N8) represents hydrogen; and wherein particular                examples of such group-SO₂—R^(S1) are —SO₂—CH₃,                —SO₂—NH₂, —SO₂—NH—CH₃);            -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1                or 2 (especially q is 0, i.e. HET¹ is linked to Ar¹ by a                direct bond); and wherein HET¹ represents                5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl),                3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing                its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl), or                5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-mercapto-[1,2,4]oxadiazol-3-yl);            -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1                (especially p is 0, i.e. HET is linked to Ar¹ by a                direct bond); and wherein HET represents a 5-membered                heteroaryl (especially oxazolyl, isoxazolyl,                oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,                imidazolyl, pyrazolyl, triazolyl, or tetrazolyl),                wherein said 5-membered heteroaryl is unsubstituted, or                mono- or di-substituted, wherein the substituents are                independently selected from (C₁₋₄)alkyl (especially                methyl), (C₁₋₄)alkoxy (especially methoxy), —COOH,                hydroxy, hydroxy-(C₁₋₃)alkyl (especially hydroxymethyl),                (C₃₋₅)cycloalkyl optionally containing one ring oxygen                atom (especially cyclopropyl, oxetan-3-yl), or                —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently                represent hydrogen, (C₁₋₃)alkyl (especially methyl), or                hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);                (especially such group —(CH₂)_(p)-HET is                1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,                2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl,                2-amino-oxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl,                5-methylamino-[1,3,4]thiadiazol-2-yl,                5-methoxy-[1,2,4]oxadiazol-3-yl,                5-amino-[1,2,4]oxadiazol-3-yl,                5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,                5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,                5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,                5-methyl-1H-imidazol-4-yl,                2,5-dimethyl-1H-imidazol-4-yl);

        -   R⁶ represents            -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl,                isopropyl, n-butyl, isobutyl);            -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,                isopropoxy, n-butoxy);            -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);            -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,                trifluoromethoxy, 2,2,2-trifluoroethoxy);            -   halogen (especially fluoro or chloro);            -   hydroxy;            -   (C₃₋₆)cycloalkyl (especially cyclopropyl);            -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,                cyclobutyl-oxy, cyclopentyl-oxy);            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);            -   —X²—NR^(N1)R^(N2), wherein X² represents a direct bond;                or X² represents —O—CH₂—CH₂—*, wherein the asterisk                indicates the bond that is linked to the —NR^(N1)R^(N2)                group; and wherein R^(N1) and R^(N2) independently                represent hydrogen, (C₁₋₄)alkyl, or (C₃₋₆)cycloalkyl;                (especially such group —X²—NR^(N1)R^(N2) represents                amino, methylamino, ethylamino, propylamino; or                2-(dimethylamino)-ethoxy);            -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl                (especially methyl, ethyl, n-propyl, isopropyl,                isobutyl), or (C₃₋₆)cycloalkyl optionally containing one                ring oxygen atom (especially cyclobutyl, oxetan-3-yl);

    -   or Ar¹ represents 8- to 10-membered bicyclic heteroaryl (notably        9- or 10-membered bicyclic heteroaryl; especially indazolyl,        benzoimidazolyl, indolyl, benzofuranyl, benzooxazolyl,        quinoxalinyl, isoquinolinyl, or quinolinyl); wherein said 8- to        10-membered bicyclic heteroaryl independently is        mono-substituted with —(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2)        represents hydrogen or (C₁₋₄)alkyl (especially methyl) (wherein        especially such group —(C₀₋₃)alkylene-COOR^(O2) is —COOH);        (especially such 8- to 10-membered bicyclic heteroaryl is        3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl,        5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl,        7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl,        6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,        3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or        2-carboxy-benzofuran-6-yl);

    -   or Ar¹ represents a group of the structure (Ar-III):

-   -   which is selected from 2-oxo-2,3-dihydro-benzooxazol-6-yl,        3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,        1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,        2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and        1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl.

The compounds of formula (I)/formula (II) may contain one or morestereogenic or asymmetric centers, such as one or more asymmetric carbonatoms, which are allowed to be present in (R)- as well as(S)-configuration. The compounds of formula (I)/formula (II) may furtherencompass compounds with one or more double bonds which are allowed tobe present in Z- as well as E-configuration and/or compounds withsubstituents at a ring system which are allowed to be present, relativeto each other, in cis- as well as trans-configuration. The compounds offormula (I)/formula (II) may thus be present as mixtures ofstereoisomers or preferably as pure stereoisomers. Mixtures ofstereoisomers may be separated in a manner known to a person skilled inthe art.

In case a particular compound (or generic structure) is designated as(R)- or (S)-enantiomer, such designation is to be understood asreferring to the respective compound (or generic structure) in enriched,especially essentially pure, enantiomeric form. Likewise, in case aspecific asymmetric center in a compound is designated as being in (R)-or (S)-configuration or as being in a certain relative configuration,such designation is to be understood as referring to the compound thatis in enriched, especially essentially pure, form with regard to therespective configuration of said asymmetric center. In analogy, cis- ortrans-designations are to be understood as referring to the respectivestereoisomer of the respective relative configuration in enriched,especially essentially pure, form. Likewise, in case a particularcompound (or generic structure) is designated as Z- or E-stereoisomer(or in case a specific double bond in a compound is designated as beingin Z- or E-configuration), such designation is to be understood asreferring to the respective compound (or generic structure) in enriched,especially essentially pure, stereoisomeric form (or to the compoundthat is in enriched, especially essentially pure, form with regard tothe respective configuration of the double bond).

The term “enriched”, when used in the context of stereoisomers, is to beunderstood in the context of the present invention to mean that therespective stereoisomer is present in a ratio of at least 70:30,especially of at least 90:10 (i.e., in a purity of at least 70% byweight, especially of at least 90% by weight), with regard to therespective other stereoisomer/the entirety of the respective otherstereoisomers.

The term “essentially pure”, when used in the context of stereoisomers,is to be understood in the context of the present invention to mean thatthe respective stereoisomer is present in a purity of at least 95% byweight, especially of at least 99% by weight, with regard to therespective other stereoisomer/the entirety of the respective otherstereoisomers.

The present invention also includes isotopically labelled, especially ²H(deuterium) labelled compounds of formula (I)/formula (II) according toembodiments 1) to 29), which compounds are identical to the compounds offormula (I)/formula (II) except that one or more atoms have each beenreplaced by an atom having the same atomic number but an atomic massdifferent from the atomic mass usually found in nature. Isotopicallylabelled, especially ²H (deuterium) labelled compounds of formula(I)/formula (II) and salts thereof are within the scope of the presentinvention. Substitution of hydrogen with the heavier isotope ²H(deuterium) may lead to greater metabolic stability, resulting e.g. inincreased in-vivo half-life or reduced dosage requirements, or may leadto reduced inhibition of cytochrome P450 enzymes, resulting e.g. in animproved safety profile. In one embodiment of the invention, thecompounds of formula (I)/formula (II) are not isotopically labelled, orthey are labelled only with one or more deuterium atoms. In asub-embodiment, the compounds of formula (I)/formula (II) are notisotopically labelled at all. Isotopically labelled compounds of formula(I)/formula (II) may be prepared in analogy to the methods describedhereinafter, but using the appropriate isotopic variation of suitablereagents or starting materials.

In this patent application, a bond drawn as a dotted line shows thepoint of attachment of the radical drawn. For example, the radical drawnbelow

is the 2-methyl-1H-indol-1-yl group.

In some instances, the compounds of formula (I)/formula (II) may containtautomeric forms. Such tautomeric forms are encompassed in the scope ofthe present invention. In case tautomeric forms exist of a certainresidue, and only one form of such residue is disclosed or defined, theother tautomeric form(s) are understood to be encompassed in suchdisclosed residue. For example the group2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl is to be understood as alsoencompassing its tautomeric forms 2-hydroxy-1H-benzo[d]imidazol-5-yl and2-hydroxy-3H-benzo[d]imidazol-5-yl. Similarly,5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (alternatively named5-oxo-4H-[1,2,4]oxadiazol-3-yl) encompasses its tautomeric form5-hydroxy-[1,2,4]oxadiazol-3-yl, and3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (alternatively named3-oxo-2H-[1,2,4]oxadiazol-5-yl) encompasses its tautomeric form3-hydroxy-[1,2,4]oxadiazol-5-yl.

Where the plural form is used for compounds, salts, pharmaceuticalcompositions, diseases and the like, this is intended to mean also asingle compound, salt, or the like.

Any reference to compounds of formula (I)/formula (II) according toembodiments 1) to 29) is to be understood as referring also to the salts(and especially the pharmaceutically acceptable salts) of suchcompounds, as appropriate and expedient.

The term “pharmaceutically acceptable salts” refers to salts that retainthe desired biological activity of the subject compound and exhibitminimal undesired toxicological effects. Such salts include inorganic ororganic acid and/or base addition salts depending on the presence ofbasic and/or acidic groups in the subject compound. For reference seefor example “Handbook of Pharmaceutical Salts. Properties, Selection andUse.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008;and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quéré(Eds.), RSC Publishing, 2012.

Definitions provided herein are intended to apply uniformly to thecompounds of formula (I)/formula (II), as defined in any one ofembodiments 1) to 22), and, mutatis mutandis, throughout the descriptionand the claims unless an otherwise expressly set out definition providesa broader or narrower definition. It is well understood that adefinition or preferred definition of a term defines and may replace therespective term independently of (and in combination with) anydefinition or preferred definition of any or all other terms as definedherein. Whenever the group Ar¹ or substituents thereof are furtherdefined, such definitions are intended to apply mutatis mutandis also tothe groups (Ar-I), (Ar-II), and (Ar-III) and their respectivesubstituents.

Whenever a substituent is denoted as optional, it is understood thatsuch substituent may be absent (i.e. the respective residue isunsubstituted with regard to such optional substituent), in which caseall positions having a free valency (to which such optional substituentcould have been attached to; such as for example in an aromatic ring thering carbon atoms and/or the ring nitrogen atoms having a free valency)are substituted with hydrogen where appropriate. Likewise, in case theterm “optionally” is used in the context of (ring) heteroatom(s), theterm means that either the respective optional heteroatom(s), or thelike, are absent (i.e. a certain moiety does not containheteroatom(s)/is a carbocycle/or the like), or the respective optionalheteroatom(s), or the like, are present as explicitly defined.

The term “halogen” means fluorine, chlorine, bromine, or iodine;especially fluorine, chlorine, or bromine; preferably fluorine orchlorine.

The term “alkyl”, used alone or in combination, refers to a saturatedstraight or branched chain hydrocarbon group containing one to sixcarbon atoms. The term “(C_(x-y))alkyl” (x and y each being an integer),refers to an alkyl group as defined before, containing x to y carbonatoms. For example a (C₁₋₆)alkyl group contains from one to six carbonatoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert.-butyl, 3-methyl-butyl, 2,2-dimethyl-propyl and3,3-dimethyl-butyl. For avoidance of any doubt, in case a group isreferred to as e.g. propyl or butyl, it is meant to be n-propyl,respectively n-butyl. Preferred are methyl and ethyl. Most preferred ismethyl. Preferred for substituents of Ar¹ being phenyl or 5- or6-membered heteroaryl are methyl, ethyl, propyl, isobutyl,1-methyl-propan-1-yl, tert.-butyl, 3-methyl-butyl.

The term “—(C_(x-y))alkylene-”, used alone or in combination, refers tobivalently bound alkyl group as defined before containing x to y carbonatoms. Preferably, the points of attachment of a —(C_(1-y))alkylenegroup are in 1,1-diyl, in 1,2-diyl, or in 1,3-diyl arrangement. In casea (C_(0-y))alkylene group is used in combination with anothersubstituent, the term means that either said substituent is linkedthrough a (C_(1-y))alkylene group to the rest of the molecule, or it isdirectly attached to the rest of the molecule (i.e. a (C₀)alkylene grouprepresents a direct bond linking said substituent to the rest of themolecule). The alkylene group —C₂He refers to —CH₂—CH₂— if notexplicitly indicated otherwise. For the linker X¹, examples of(C₁₋₃)alkylene groups are —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, and —CH₂—CH₂—,especially —CH₂— and —CH₂—CH₂—. Examples of (C₀₋₃)alkylene groups asused in the substituents —(C₀₋₃)alkylene-COOR^(O2) and(C₀₋₃)alkylene-COOR^(O3), respectively, are (C₀)alkylene, and methylene,respectively.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O—group wherein the alkyl group is as defined before. The term“(C_(x-y))alkoxy” (x and y each being an integer) refers to an alkoxygroup as defined before containing x to y carbon atoms. For example a(C₁₋₄)alkoxy group means a group of the formula (C₁₋₄)alkyl-O— in whichthe term “(C₁₋₄)alkyl” has the previously given significance. Examplesof alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy andespecially methoxy. Preferred for substituents of Ar¹ being phenyl or 5-or 6-membered heteroaryl are methoxy, ethoxy, propoxy, butoxy,isobutoxy.

The term “fluoroalkyl”, used alone or in combination, refers to an alkylgroup as defined before containing one to three carbon atoms in whichone or more (and possibly all) hydrogen atoms have been replaced withfluorine. The term “(C_(x-y))fluoroalkyl” (x and y each being aninteger) refers to a fluoroalkyl group as defined before containing x toy carbon atoms. For example a (C₁₋₃)fluoroalkyl group contains from oneto three carbon atoms in which one to seven hydrogen atoms have beenreplaced with fluorine. Representative examples of fluoroalkyl groupsinclude trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and2,2,2-trifluoroethyl. Preferred are (C₁)fluoroalkyl groups such astrifluoromethyl. An example of “(C₁₋₃)fluoroalkyl, wherein said(C₁₋₃)fluoroalkyl is optionally substituted with hydroxy” is2,2,2-trifluoro-1-hydroxy-ethyl.

The term “fluoroalkoxy”, used alone or in combination, refers to analkoxy group as defined before containing one to three carbon atoms inwhich one or more (and possibly all) hydrogen atoms have been replacedwith fluorine. The term “(C_(x-y))fluoroalkoxy” (x and y each being aninteger) refers to a fluoroalkoxy group as defined before containing xto y carbon atoms. For example a (C₁₋₃)fluoroalkoxy group contains fromone to three carbon atoms in which one to seven hydrogen atoms have beenreplaced with fluorine. Representative examples of fluoroalkoxy groupsinclude trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy,2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are(C₁)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy, aswell as 2,2,2-trifluoroethoxy.

The term “cycloalkyl”, used alone or in combination, refers to asaturated monocyclic hydrocarbon ring containing three to six carbonatoms. The term “(C_(x-y))cycloalkyl” (x and y each being an integer),refers to a cycloalkyl group as defined before containing x to y carbonatoms. For example a (C₃₋₆)cycloalkyl group contains from three to sixcarbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and cycloheptyl. Preferred are cyclopropyl,cyclobutyl, and cyclopentyl; especially cyclopropyl. An example ofcycloalkyl groups containing one ring oxygen atom is especiallyoxetanyl. Examples of (C₃₋₆)cycloalkyl groups wherein said(C₃₋₆)cycloalkyl is optionally mono-substituted with amino arecyclopropyl, 1-amino-cyclopropyl. Examples of (C₃₋₆)cycloalkyl groupswherein said (C₃₋₆)cycloalkyl is mono-substituted with —COOH are1-carboxy-cyclopropyl, 1-carboxy-cyclopentyl.

The term “—(C_(x-y))cycloalkylene-”, used alone or in combination,refers to bivalently bound cycloalkyl group as defined before containingx to y carbon atoms. Preferably, the points of attachment of anybivalently bound cycloalkyl group are in 1,1-diyl, or in 1,2-diylarrangement. Examples are cyclopropan-1,1-diyl, cyclopropan-1,2-diyl,and cyclopentan-1,1-diyl; preferred is cyclopropan-1,1-diyl.

Examples of (C₃₋₆)cycloalkyl-oxy are cyclobutyl-oxy, andcyclopentyl-oxy.

Alkylated amino groups —N[(C₁₋₄)alkyl]₂ as used in groups —X¹—CO—R^(O1),wherein R^(O1) represents —O—CH₂—CO—R^(O4), wherein R^(O4) represents—N[(C₁₋₄)alkyl]₂; or wherein R^(O1) represents—O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ are such that the two respective (C₁₋₄)alkylgroups are independently selected. A preferred example of such aminogroup —N[(C₁₋₄)alkyl]₂ is —N(CH₃)₂.

The term “heterocycle”, used alone or in combination, and if notexplicitly defined in a broader or more narrow way, refers to asaturated monocyclic hydrocarbon ring containing one or two (especiallyone) ring heteroatoms independently selected from nitrogen, sulfur, andoxygen (especially one nitrogen atom, two nitrogen atoms, one nitrogenatom and one oxygen atom, or one nitrogen atom and one sulfur atom). Theterm “(C_(x-y))heterocycle” refers to such a heterocycle containing x toy ring atoms. Heterocycles are unsubstituted or substituted asexplicitly defined.

Examples of the Fragment:

wherein ring (A) represents an aromatic 5- or 6-membered ring which ring(A) is fused to the phenyl group, wherein said ring (A) optionallycontains one or two heteroatoms independently selected from nitrogen,oxygen, and sulfur are indolyl, isoindolyl, benzofuranyl,isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl,quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, andphthalazinyl; notably benzofuranyl, benzothiophenyl, benzothiazolyl,benzoisothiazolyl, indolyl, indazolyl, naphthyl, quinolinyl, andisoquinolinyl. The above groups are unsubstituted or substituted asexplicitly defined.Examples of the Fragment:

wherein ring (A) represents a non-aromatic 5- to 7-membered ring, whichring (A) is fused to the phenyl group, wherein independently said ring(A) optionally contains one or two heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur are 2,3-dihydro-benzo[b]thiophenyl,benzo[1,3]dioxolyl, 1,3-dihydro-isobenzofuranyl,2,3-dihydro-benzofuranyl, indanyl, 5,6,7,8-tetrahydro-naphthalenyl,2,3-dihydro-benzo[1,4]dioxinyl, chromanyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, 1,2,3,4-tetrahydro-quinolinyl, and3,4-dihydro-2H-benzo[b][1,4]dioxepinyl. The above groups areunsubstituted or substituted as explicitly defined.

A group composed of a “non-aromatic 5- or 6-membered ring fused to thephenyl group, wherein ring (B) comprises one or two heteroatomsindependently selected from nitrogen and oxygen” as used for (Ar-III)refers to phenyl groups which are fused to a (C₅₋₆)heterocycle asdefined before. Examples are 2,3-dihydro-benzofuranyl,2,3-dihydro-1H-indolyl, 2,3-dihydro-benzo[1,4]dioxinyl,2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl,2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydro-isoindolyl,3-dihydro-benzooxazol-6-yl, 2,3-dihydro-benzooxazol-5-yl,1,2,3,4-tetrahydro-quinazolin-6-yl, 1,2,3,4-tetrahydro-quinazolin-7-yl,1,2,3,4-tetrahydro-isoquinolin-6-yl, and1,2,3,4-tetrahydro-phthalazin-6-yl. The above groups are unsubstituted,mono-, or di-substituted, wherein the substituents are independentlyselected from oxo, (C₁₋₆)alkyl, and —(C₀₋₃)alkylene-COOR^(O3) whereinR^(O3) represents hydrogen or (C₁₋₃)alkyl (especially methyl);especially substituents are independently selected from oxo, methyl,ethyl, propyl, butyl, isobutyl, or —COOH; wherein the substituents areattached to the fused 5- or 6-membered non-aromatic ring. Oxosubstituents are preferably attached to a ring carbon atom which is inalpha position to a ring nitrogen atom. Preferred examples of suchgroups are 2,3-dihydro-benzofuranyl, 2,3-dihydro-1H-indolyl,2,3-dihydro-benzo[1,4]dioxinyl; as well as the oxosubstitutedheterocyclyl groups 3-oxo-2,3-dihydro-1H-indazolyl,2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl,3-oxo-2,3-dihydrobenzo[d]isoxazolyl, 2-oxo-1,3-dihydro-indolyl,1-oxo-2,3-dihydro-isoindolyl, 2-oxo-2,3-dihydro-benzooxazolyl,2-oxo-1,2,3,4-tetrahydro-quinazolinyl,1-oxo-1,2,3,4-tetrahydro-isoquinolinyl,1,4-dioxo-1,2,3,4-tetrahydro-phthalazinyl; wherein the above groupsoptionally carry one (further) substituent independently selected from(C₁₋₆)alkyl, and —(C₀₋₃)alkylene-COOR^(O3) wherein R^(O3) representshydrogen or (C₁₋₃)alkyl (especially methyl). Particular examples are2-oxo-2,3-dihydro-benzooxazol-6-yl,3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl.

For avoidance of doubt, certain groups having tautomeric forms which areconsidered predominantly non-aromatic, such as for example2-oxo-2,3-dihydro-1H-benzo[d]imidazolyl groups, are defined herein as 8-to 10-membered partially aromatic fused bicyclic heterocyclyl groups,even though their corresponding tautomeric form(2-hydroxy-1H-benzo[d]imidazolyl) could also be considered as a 8- to10-membered bicyclic heteroaryl group.

The term “aryl”, used alone or in combination, means phenyl or naphthyl,especially phenyl. The above-mentioned aryl groups are unsubstituted orsubstituted as explicitly defined.

Examples of the substituent Ar¹ representing phenyl are especially thosewhich are at least mono-substituted in para position with respect to thepoint of attachment of the rest of the molecule. In addition, such groupAr¹ representing phenyl may carry one or two further substituents,especially in one or both meta positions with respect to the point ofattachment of the rest of the molecule. The respective substituents ofsuch phenyl groups are as explicitly defined.

The term “heteroaryl”, used alone or in combination, means a 5- to10-membered monocyclic or bicyclic aromatic ring containing one to amaximum of four heteroatoms, each independently selected from oxygen,nitrogen and sulfur. Examples of such heteroaryl groups are 5-memberedheteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl,thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl; 6-membered heteroaryl groups such aspyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; and 8- to 10-memberedbicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl,isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl,quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl,imidazopyridazinyl, and imidazothiazolyl. The above-mentioned heteroarylgroups are unsubstituted or substituted as explicitly defined.

For the substituent Ar¹ representing a “5- or 6-membered heteroaryl”,the term means the above-mentioned 5- or 6-membered groups such asespecially pyridinyl, pyrimidinyl, pyrrolyl, pyrazolyl, isoxazolyl,thiazolyl or thiophenyl. Notably, the term refers to 5-membered groupssuch as especially thiazolyl or thiophenyl; in particular thiophen-2-yl,thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl. Preferred isthiophenyl, especially thiophen-2-yl; or thiazolyl, especiallythiazol-2-yl. The above groups are substituted as explicitly defined.Thiophen-2-yl or thiazol-2-yl are especially di-substituted with onesubstituent being in position 5, and a second substituent in position 4(and, for thiophen-2-yl, optionally a halogen substituent in position3).

For the substituent Ar¹ representing a “8- to 10-membered bicyclicheteroaryl” the term means the above-mentioned 8- to 10-memberedheteroaryl groups. Notably, the term refers to 9- or 10-memberedheteroaryl groups, such as especially indazolyl, benzoimidazolyl,indolyl, benzotriazolyl, benzooxazolyl, quinoxalinyl, isoquinolinyl,quinolinyl, pyrrolopyridinyl, and imidazopyridinyl, as well asbenzofuranyl, benzothiophenyl, and benzothiazolyl. The above groups areunsubstituted or substituted as explicitly defined. Particular examplesare 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl,1H-indol-6-yl, 1-methyl-1H-indol-5-yl, 1H-indazol-5-yl, 1H-indazol-6-yl,1-methyl-1H-indazol-6-yl, 3-methyl-1H-indazol-6-yl,3-methoxy-1H-indazol-6-yl, 6-methoxy-1H-indazol-5-yl,1H-benzoimidazol-5-yl, 2-methyl-1H-benzoimidazol-5-yl,2-trifluoromethyl-1H-benzoimidazol-5-yl, 1H-benzotriazol-5-yl,2-methyl-benzooxazol-5-yl, 2-methyl-benzooxazol-6-yl, quinoxalin-6-yl,isoquinolin-7-yl, quinolin-6-yl, 1H-pyrrolo[2,3-c]pyridin-3-yl,1H-pyrrolo[2,3-b]pyridin-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl,1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl, imidazo[1,2-a]pyridin-6-yl,2-carboxy-1H-indol-5-yl, 3-carboxy-1H-indol-6-yl,4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl,6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl,7-carboxy-1H-indol-4-yl, 7-carboxy-1-methyl-1H-indol-4-yl,5-(methoxycarbonyl)-1H-indol-2-yl, 6-(methoxycarbonyl)-1H-indol-2-yl),6-carboxy-benzofuran-2-yl, 3-carboxy-benzofuran-6-yl,2-carboxy-benzofuran-5-yl, and 2-carboxy-benzofuran-6-yl. Preferredexamples are 1H-benzoimidazol-5-yl, 1H-indol-6-yl, 1H-indol-5-yl,1H-indol-2-yl, 1H-indazol-5-yl, as well as 8- to 10-membered bicyclicheteroaryl which are mono-substituted with —(C₀₋₃)alkylene-COOR^(O2)such as 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl,5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl,7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl,6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, and2-carboxy-benzofuran-6-yl, and, in addition, 3-carboxy-1H-indazol-6-yl,and 7-carboxy-1H-indol-4-yl.

For the substituent “—(CH₂)_(p)-HET, wherein p represents the integer 0or 1, and wherein HET represents a 5- or 6-membered heteroaryl”, such 5-or 6-membered heteroaryl is as defined before; notably a nitrogencontaining 5-membered heteroaryl such as especially tetrazolyl, oroxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, imidazolyl, pyrazolyl, or triazolyl. The above groups areunsubstituted or substituted as explicitly defined. The group—(CH₂)_(p)— is preferably absent, i.e. p represents the integer 0 andthe group HET is directly bound to Ar¹. Particular examples of—(CH₂)_(p)-HET are especially the —(CH₂)₀-HET groups 1H-tetrazol-5-yl,3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl; furtherexamples are 3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,5-amino-[1,3,4]thiadiazol-2-yl, 5-methylamino-[1,3,4]thiadiazol-2-yl,5-methoxy-[1,2,4]oxadiazol-3-yl, 5-amino-[1,2,4]oxadiazol-3-yl,5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,5-methyl-1H-imidazol-4-yl, and 2,5-dimethyl-1H-imidazol-4-yl; as well as1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 3-methyl-pyrazol-1-yl,1-methyl-1H-pyrazol-3-yl, 5-methyl-1H-pyrazol-3-yl,3,5-dimethyl-pyrazol-1-yl, 4-carboxy-1H-pyrazol-3-yl, 1H-imidazol-2-yl,3-methyl-3H-imidazol-4-yl, 2-methyl-1H-imidazol-4-yl,1,5-dimethyl-1H-imidazol-2-yl, 1,2-dimethyl-1H-imidazol-4-yl,1,5-dimethyl-1H-imidazol-4-yl, 2-cyclopropyl-1H-imidazol-4-yl,2-cyclopropyl-1-methyl-1H-imidazol-4-yl, [1,2,4]oxadiazol-5-yl,5-methyl-[1,2,4]oxadiazol-3-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,5-methyl-[1,3,4]oxadiazol-2-yl, isothiazol-5-yl, thiazol-2-yl,thiazol-4-yl, 4-methyl-thiazol-2-yl, 2-methyl-thiazol-4-yl,2-amino-5-methyl-thiazol-4-yl, 4,5-dimethyl-thiazol-2-yl,4-carboxy-thiazol-2-yl, 2-carboxy-thiazol-4-yl, 2-hydroxy-thiazol-4-yl,2-amino-2-oxoethyl)thiazol-4-yl, isoxazol-3-yl, isoxazol-5-yl,3-methyl-isoxazol-5-yl, 4-methyl-isoxazol-5-yl,4-carboxy-3-methyl-isoxazol-5-yl, oxazol-5-yl, 2-methyl-oxazol-5-yl,2-(2-carboxyethyl)-oxazol-5-yl, 2-(2-carboxyethyl)-4-methyl-oxazol-5-yl,4H-[1,2,4]triazol-3-yl, 1H-[1,2,4]triazol-1-yl,2-methyl-2H-[1,2,4]triazol-3-yl, pyridin-2-yl, 4-fluoro-pyridin-2-yl,pyrimidin-2-yl, 5-fluoro-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl,4-methoxy-pyrimidin-2-yl, 6-methoxy-pyrimidin-4-yl,6-dimethylamino-pyrimidin-4-yl, pyrazin-2-yl, 6-methoxy-pyrazin-2-yl,6-methoxy-pyridazin-3-yl, 3H-imidazol-4-yl, 3H-[1,2,3]triazol-4-yl,oxazol-2-yl, and 4,5-dimethyl-oxazol-2-yl. For avoidance of doubt,certain groups having tautomeric forms which may be consideredpredominantly aromatic (such as for example 3-hydroxy-isoxazolyl or2-hydroxy-[1,3,4]oxadiazolyl groups) are defined herein as heteroarylgroups HET, even though their corresponding tautomeric form(3-oxo-2,3-dihydro-2H-isoxazolyl, respectively,2-oxo-2,3-dihydro-3H-[1,3,4]oxadiazolyl) could also be considered as anon-aromatic group. Likewise, certain groups having tautomeric formswhich may be considered predominantly non-aromatic (such as5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl or5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl) as defined for thesubstituent HET¹, are defined herein as not being part of substitutedheteroaryl groups as defined for HET, even though their correspondingtautomeric form (5-hydroxy-[1,2,4]oxadiazolyl, respectively,5-mercapto-[1,2,4]oxadiazolyl), could also be considered as anheteroaryl group. It is understood that the corresponding tautomer isencompassed in the respective scope as defined.

The term “cyano” refers to a group —CN.

The term “oxo” refers to a group ═O which is preferably attached to achain or ring carbon or sulfur atom as for example in a carbonyl group—(CO)—, or a sulfonyl group —(SO₂)—.

Examples of “—X²—NR^(N1)R^(N2)” groups as used for substituents of Ar¹being phenyl or 5- or 6-membered heteroaryl are amino, methylamino,ethylamino, propylamino, amino-methyl, methylamino-methyl,isobutylamino-methyl, cyclopropylamino-methyl, cyclobutylamino-methyl,(2-methoxyethyl)amino-methyl, (2,2,2-trifluoro-ethyl)-amino; or—NH—CO—H, —N(C₂H₅)—CO—H, —NH—CO—C₂H₅, —NH—CO—CH₂—CH₂—OH, —NH—CO—O—CH₃,—N(CH₃)—CO—O—CH₃; or pyrrolidin-1-yl, 2-oxo-pyrrolidin-1-yl,1,1-dioxo-isothiazolidin-2-yl, morpholin-4-yl, azetidin-1-yl, orpiperidin-1-yl; and 2-(dimethylamino)-ethoxy.

Examples of a group “—NH—CO—NR^(N5)R^(N6)” as used for substituents ofthe group Ar¹ are ureido (—NH—CO—NH₂) and 3-ethylureido(—NH—CO—NH—C₂H₅).

Examples of a group “—(CH₂)_(r)CO—NR^(N3)R^(N4) wherein r represents theinteger 0 or 1” as used for substituents of the group Ar¹ are preferablygroups wherein r represents the integer 0 and at least one of R^(N3) andR^(N4) represents hydrogen (or less preferred, methyl). Particularexamples of such group —CO—NR^(N3)R^(N4) are —CO—NH₂, —CO—NH(CH₃),—CO—N(CH₃)₂, —CO—NH(C₂H₅), —CO—NH—O-methyl, —CO—NH—O-ethyl,—CO—NH—O-isopropyl, —CO—NH—C₂H₄—OH, —CO—NH—O—C₂H₄—OH, —CO—NH—C₂H₄—OCH₃,—CO—NH—C₂H₄—N(CH₃)₂, and —CO—NH—O-benzyl. Further examples are—CO—NH-isopropyl and —CO—NH—OH, as well as —CO—N(CH₃)₂.

Examples of a group “—X¹—CO—R^(O1)” as used for substituents of thegroup Ar¹ are especially the following groups:

-   -   a) X¹ represents a direct bond; and R^(O1) represents —OH; (i.e.        —X¹—CO—R^(O1) represents —COOH); or    -   b) X¹ represents a direct bond; and R^(O1) represents        —O—(C₁₋₄)alkyl (especially ethoxy, or methoxy); (i.e.        —X¹—CO—R^(O1) represents —CO—(C₁₋₄)alkoxy (especially        ethoxycarbonyl, methoxycarbonyl)); or    -   c) X¹ represents a direct bond; and R^(O1) represents        —NH—SO₂—R^(S3); wherein R^(S3) represents (C₁₋₄)alkyl;        (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionally        contains a ring oxygen atom; (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene        wherein the (C₃₋₆)cycloalkyl optionally contains a ring oxygen        atom; (C₁₋₃)fluoroalkyl; phenyl; or —NH₂; (i.e. —X¹—CO—R^(O1)        represents —CO—NH—SO₂—R^(S3) wherein R^(S3) represents the above        mentioned groups; notably methyl, ethyl, isopropyl, cyclopropyl,        trifluoromethyl, amino; especially —X¹—CO—R^(O1) represents        —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂, —CO—NH—SO₂-cyclopropyl,        —CO—NH—SO₂-ethyl, or —CO—NH—SO₂—NH₂); or    -   d) X¹ represents (C₁₋₃)alkylene (especially —CH₂—, —CH₂—CH₂—),        —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*, —O—CH(CH₃)—*,        —O—C(CH₃)₂—*, O—CH₂—CH₂—*), —NH—(C₁₋₃)alkylene-* (especially        —NH—CH₂*, —NH—CH(CH₃)—*), —S—CH₂*, —CF₂—, —CH═CH—, or —CH═CH—        [in a sub-embodiment X¹ represents especially —O—CH₂*,        —NH—CH₂—*, —S—CH₂—*, or (C₁₋₃)alkylene]; wherein the asterisks        indicate the bond that is linked to the —CO—R^(O1) group; and        R^(O1) represents —OH (i.e. —X¹—CO—R^(O1) represents —X¹—COOH        wherein X¹ represents the above mentioned groups; especially        —X¹—CO—R^(O1) represents —O—CH₂—COOH or —NH—CH₂—COOH; as well as        —CH₂—COOH, —CH₂—CH₂—COOH, —CH═CH—COOH, —CH═CH—OOH,        —O—CH₂—CH₂—OOH, —O—CH(CH₃)—COOH, or —NH—CH(CH₃)—COOH); or    -   e) —X¹ represents —NH—CO—* or —CO—; wherein the asterisk        indicates the bond that is linked to the —CO—R^(O1) group; and        R^(O1) represents —OH (i.e. —X¹—CO—R^(O1) represents —X¹—COOH        wherein X¹ represents the above mentioned groups; especially        —X¹—CO—R^(O1) represents —NH—CO—OOH, —CO—COOH); or    -   f) X¹ represents (C₃₋₅)cycloalkylene; and R^(O1) represents —OH;        (i.e. —X¹—CO—R^(O1) represents (C₃₋₆)cycloalkyl which is        mono-substituted with COOH; especially —X¹—CO—R^(O1) represents        1-carboxy-cyclopropan-1-yl or 1-carboxy-cyclopentan-1-yl); or    -   g) X¹ represents a direct bond; and R^(O1) represents        —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy, or        (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂; especially —X¹—CO—R^(O1)        represents —CO—O—CH₂—COOH; or        wherein each of the groups a), b), c), d), e), f), and g) forms        a particular sub-embodiment.

Compounds of Formula (I)/formula (II) containing a group “—X¹—CO—R^(O1)”wherein X¹ represents —CH═CH— may be in E- or Z-configuration.Preferably, such groups are in E-configuration.

Whenever a group Ar¹ is substituted with a substituent comprising acarboxylic acid group —COOH (such as in the substituents—(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2) represents hydrogen;—(C₀₋₃)alkylene-COOR^(O3) wherein R^(O3) represents hydrogen; or in thesubstituents —X¹—CO—R^(O1) wherein R^(O1) represents —OH, especially inthe —X¹—CO—R^(O1) groups a), d), e) and f) above) such carboxylic acidgroup may be present in form of a prodrug group. Such prodrugs areencompassed in the scope of the present invention. In certain instances,compounds comprising such carboxylic acid prodrug groups may as suchexhibit biological activity on the EP2 and/or EP4 receptor, whereas inother instances, such compounds comprising such carboxylic acid prodruggroups require (e.g. enzymatic) cleavage of the prodrug to exhibitbiological activity on the EP2 and/or EP4 receptor. Prodrugs of thecarboxylic acid functional group are well known in the art (see forexample J. Rautio (Ed.) Prodrugs and Targeted Delivery: Towards BetterADME Properties, Volume 47, Wiley 2010, ISBN: 978-3-527-32603-7; H. Maagin Stella, V., Borchardt, R., Hageman, M., Oliyai, R., Maag, H., Tilley,J. (Eds.) Prodrugs: Challenges and Rewards, Springer 2007, ISBN978-0-387-49785-3).

Particular examples of prodrugs, for example suitable for —X¹—COOHgroups are:

-   -   ester groups —X¹—CO—O—P¹ wherein P¹ is for example (C₁₋₄)alkyl;        (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionally        contains a ring oxygen atom; (C₃₋₆)cycloalkyl-(C₁₋₃)alkyl        wherein the (C₃₋₆)cycloalkyl optionally contains a ring oxygen        atom; (C₁₋₃)fluoroalkyl; hydroxy-(C₂₋₄)alkyl; or        (C₁₋₄)alkoxy-(C₂₋₄)alkyl (especially P¹ is (C₁₋₄)alkyl, in        particular methyl or ethyl);    -   groups —X¹—CO—NH—SO₂—R^(S3) wherein R^(S3) represents        (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl        optionally contains a ring oxygen atom;        (C₃₋₆)cycloalkyl-(C₁₋₃)alkyl wherein the (C₃₋₆)cycloalkyl        optionally contains a ring oxygen atom; (C₁₋₃)fluoroalkyl, —NH₂;        (especially R^(S3) is (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl; in        particular methyl);    -   groups —X¹—CO—R^(O1) wherein R^(O1) represents —O—CH₂—CO—R^(O4),        wherein R^(O4) represents hydroxy, or (C₁₋₄)alkoxy, or        —N[(C₁₋₄)alkyl]₂ (especially —CO—O—CH₂—COOH,        —CO—O—CH₂—CO—N(CH₃)₂);    -   groups —X¹—CO—R^(O1) wherein R^(O1) represents        —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents (C₁₋₄)alkyl or        (C₁₋₄)alkoxy (especially —CO—O—CH₂—O—CO—O-ethyl,        —CO—O—CH₂—O—CO-propyl);    -   groups —X¹—CO—R^(O1) wherein R^(O1) represents        —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially —CO—O—CH₂—CH₂—N(CH₃)₂);        and    -   groups —X¹—CO—R^(O1) wherein R^(O1) represents        5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-.

Examples of “hydroxy-(C₁₋₄)alkyl” groups as used for substituents of thegroup Ar¹ are hydroxymethyl and 1-hydroxy-ethyl.

An example of “dihydroxy-(C₂₋₄)alkyl” groups as used for substituents ofthe group Ar¹ is 1,2-dihydroxyethyl.

An example of “hydroxy-(C₂₋₄)alkoxy” groups as used for substituents ofthe group Ar¹ is 2-hydroxy-ethoxy.

An example of “(C₁₋₄)alkoxy-(C₂₋₄)alkoxy” groups as used forsubstituents of the group Ar¹ is 2-methoxy-ethoxy.

Examples of a group “—SO₂—R^(S1)” as used for substituents of the groupAr¹ are —SO₂—CH₃, —SO₂—NH₂, —SO₂—NH—CH₃.

Examples of a group “S—R^(S2)” as used for substituents of the group Ar¹are methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl,isobutylsulfanyl), cyclobutylsulfanyl, and (oxetan-3-yl)-sulfanyl.

An example of a “(C₁₋₄)alkoxy-(C₂₋₄)alkyl” group is 2-methoxyethyl.

An example of a “hydroxy-(C₂₋₄)alkoxy” group is 2-hydroxy-ethoxy.

An example of a “hydroxy-(C₂₋₄)alkyl” group is 2-hydroxy-ethyl.

An example of a “—CO—(C₁₋₄)alkoxy” group as used for substituents of thegroup Ar¹ is ethoxycarbonyl. Such groups may also be useful as prodrugsof the respective —COOH substituent.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range; or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C., andpreferably to an interval extending from Y minus 5° C. to Y plus 5° C.Besides, the term “room temperature” as used herein refers to atemperature of about 25° C.

Further embodiments of the invention are presented hereinafter:

9) Another embodiment relates to compounds of formula (II) according toembodiment 8), wherein R³ represents hydrogen.

10) Another embodiment relates to compounds of formula (II) according toembodiment 8), wherein R³ represents methyl.

11) Another embodiment relates to compounds according to any one ofembodiments 8) to 10), wherein Ar represents

-   -   a phenyl group of the structure (Ar-I):

-   -   wherein        -   R^(p) represents            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -    -OH;                -    —O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -    —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, or —NH₂;                -    -O—CH₂—CO—R^(O4), wherein R^(O4) represents                    hydroxy, or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;                -    -O—CH₂—O—CO—R^(O5), wherein R^(O5) represents                    (C₁₋₄)alkyl or (C₁₋₄)alkoxy;                -    -O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂ (especially                    —O—CH₂—CH₂—N(CH₃)₂); or                -    (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CO—O—CH₂—COOH, —CO—O—CH₂—CH₂—N(CH₃)₂,                —CO—O—CH₂—CO—N(CH₃)₂, —CO—O—CH₂—O—CO—O—C₂H₅,                —CO—O—CH₂—O—CO-propyl,                (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyl-O—CO—,                —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH,                —CH═CH—COOH, —NH—CO—COOH, 1-carboxy-cyclopropan-1-yl];

-   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;        -   —CO—NR^(N3)R^(N4) wherein R^(N3) and R^(N4) independently            represent hydrogen, or (C₁₋₄)alkyl, (wherein preferably at            least one of R^(N3) and R^(N4) represents hydrogen; and            wherein particular examples of such group —CO—NR^(N3)R^(N4)            are —CO—NH₂, —CO—NH(CH₃), or —CO—NH(C₂H₅));        -   NH—CO—NR^(N)R^(N6) wherein R^(N5) and R^(N6) independently            represent hydrogen or (C₁₋₄)alkyl (wherein preferably at            least one of R^(N5) and R^(N6) represents hydrogen; and            wherein particular examples of such group            —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);        -   (CH₂)_(q)-HET¹, wherein q represents the integer 0, 1 or 2            (especially q is 0, i.e. HET is linked to Ar¹ by a direct            bond); and wherein HET¹ represents            5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing its            tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or            3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing its            tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl),        -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1            (especially p is 0, i.e. HET is linked to Ar¹ by a direct            bond); and wherein HET represents a 5-membered heteroaryl            (especially oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,            isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,            triazolyl, or tetrazolyl), wherein said 5-membered            heteroaryl is unsubstituted, or mono- or di-substituted,            wherein the substituents are independently selected from            (C₁₋₄)alkyl (especially methyl), (C₁₋₄)alkoxy (especially            methoxy), —COOH, hydroxy, hydroxy-(C₁₋₃)alkyl (especially            hydroxymethyl), (C₃₋₅)cycloalkyl optionally containing one            ring oxygen atom (especially cyclopropyl, oxetan-3-yl), or            —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently            represent hydrogen, (C₁₋₃)alkyl (especially methyl), or            hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);            (especially such group —(CH₂)_(p)-HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, 2-hydroxy-[1,3,4]oxadiazol-4-yl,            3-amino-isoxazol-5-yl, 2-amino-oxazol-5-yl,            5-amino-[1,3,4]thiadiazol-2-yl,            5-methylamino-[1,3,4]thiadiazol-2-yl,            5-methoxy-[1,2,4]oxadiazol-3-yl,            5-amino-[1,2,4]oxadiazol-3-yl,            5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,            5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,            5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,            5-methyl-1H-imidazol-4-yl, 2,5-dimethyl-1H-imidazol-4-yl)            [in particular HET is unsubstituted or mono-substituted with            hydroxy; especially HET is 1H-tetrazol-5-yl,            3-hydroxy-isoxazol-5-yl, or            2-hydroxy-[1,3,4]oxadiazol-4-yl];        -   R^(m1) represents            -   hydrogen;            -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl,                isopropyl, n-butyl, isobutyl);            -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,                isopropoxy, n-butoxy, isobutoxy);            -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);            -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,                trifluoromethoxy, 2,2,2-trifluoroethoxy);            -   halogen (especially fluoro or chloro);            -   (C₃₋₆)cycloalkyl (especially cyclopropyl);            -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,                cyclobutyl-oxy, cyclopentyl-oxy);            -   hydroxy;            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);            -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl                (especially methyl, ethyl, n-propyl, isopropyl,                isobutyl), (C₃₋₆)cycloalkyl optionally containing one                ring oxygen atom (especially cyclobutyl, oxetan-3-yl);        -   wherein in a sub-embodiment, R^(m1) especially is different            from hydrogen;        -   R^(m2) represents hydrogen, methyl, fluoro, or chloro; and        -   R^(o1) represents hydrogen;

    -   or Ar¹ represents a 5-membered heteroaryl group of the structure        (Ar-I):

-   -   wherein        -   Y represents CH or N;        -   R⁷ represents            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂—*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -    -OH;                -    -O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -    —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₁₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —OOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CH₂—COOH, —CH₂—CO—O—CH₃, CH₂—CO—O—C₂H₅, —CH(CH₃)—COOH,                —CH₂—CH₂—COOH, —CH═CH—COOH, —NH—CO—COOH,                —NH—CH(CH₃)—COOH, —NH—CH₂—CO—O—CH₃,                1-carboxy-cyclopropan-1-yl];

-   -   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;            -   —CO—NR^(N3)R^(N4) wherein R^(N3) and R^(N4)                independently represent hydrogen, or (C₁₋₄)alkyl                (wherein preferably at least one of R^(N3) and R^(N4)                represents hydrogen; and wherein particular examples of                such group —CO—NR^(N3)R^(N4) are —CO—NH₂, —CO—NH(CH₃),                or —CO—NH(C₂H₅);            -   NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6)                independently represent hydrogen or (C₁₋₄)alkyl (wherein                preferably at least one of R^(N5) and R^(N6) represents                hydrogen; and wherein particular examples of such group                —NH—CO—NR^(N5)R^(N6) are —NH—CO—NH₂, —NH—CO—NH—C₂H₅);            -   —(CH₂)_(q)-HET¹, wherein q represents the integer 0, 1                or 2 (especially q is 0, i.e. HET¹ is linked to Ar¹ by a                direct bond); and wherein HET¹ represents                5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl),                3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing                its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl);            -   —(CH₂)_(p)-HET, wherein p represents the integer 0 or 1                (especially p is 0, i.e. HET is linked to Ar¹ by a                direct bond); and wherein HET represents a 5-membered                heteroaryl (especially oxazolyl, isoxazolyl,                oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,                imidazolyl, pyrazolyl, triazolyl, or tetrazolyl),                wherein said 5-membered heteroaryl is unsubstituted, or                mono- or di-substituted, wherein the substituents are                independently selected from (C₁₋₄)alkyl (especially                methyl), (C₁₋₄)alkoxy (especially methoxy), —COOH,                hydroxy, hydroxy-(C₁₋₃)alkyl (especially hydroxymethyl),                (C₃₋₅)cycloalkyl optionally containing one ring oxygen                atom (especially cyclopropyl, oxetan-3-yl), or                —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently                represent hydrogen, (C₁₋₃)alkyl (especially methyl), or                hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);                (especially such group —(CH₂)_(p)-HET is                1H-tetrazol-5-yl, 3-hydroxy-isoxazol-5-yl,                2-hydroxy-[1,3,4]oxadiazol-4-yl, 3-amino-isoxazol-5-yl,                2-amino-oxazol-5-yl, 5-amino-[1,3,4]thiadiazol-2-yl,                5-methylamino-[1,3,4]thiadiazol-2-yl,                5-methoxy-[1,2,4]oxadiazol-3-yl,                5-amino-[1,2,4]oxadiazol-3-yl,                5-[(2-hydroxy-ethyl)]-amino)-[1,2,4]oxadiazol-3-yl,                5-hydroxymethyl-[1,2,4]oxadiazol-3-yl,                5-(oxetan-3-yl)-[1,2,4]oxadiazol-3-yl, 1H-imidazol-4-yl,                5-methyl-1H-imidazol-4-yl,                2,5-dimethyl-1H-imidazol-4-yl) [in particular HET is                unsubstituted or mono-substituted with hydroxy;                especially HET is 1H-tetrazol-5-yl,                3-hydroxy-isoxazol-5-yl, or                2-hydroxy-[1,3,4]oxadiazol-4-yl];

        -   R⁶ represents            -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl,                isopropyl, n-butyl, isobutyl);            -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,                isopropoxy, n-butoxy);            -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);            -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,                trifluoromethoxy, 2,2,2-trifluoroethoxy);            -   halogen (especially fluoro or chloro);            -   hydroxy;            -   (C₃₋₆)cycloalkyl (especially cyclopropyl);            -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,                cyclobutyl-oxy, cyclopentyl-oxy);            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);            -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl                (especially methyl, ethyl, n-propyl, isopropyl,                isobutyl), or (C₃₋₆)cycloalkyl optionally containing one                ring oxygen atom (especially cyclobutyl, oxetan-3-yl);

    -   or Ar¹ represents 3-carboxy-1H-indol-6-yl,        4-carboxy-1H-indol-2-yl, 5-carboxy-1H-indol-2-yl,        6-carboxy-1H-indol-2-yl, 7-carboxy-1H-indol-2-yl,        5-(methoxycarbonyl)-1H-indol-2-yl,        6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,        3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or        2-carboxy-benzofuran-6-yl;

    -   or Ar¹ represents a group of the structure (Ar-III):

-   -   wherein ring (B) represents 2-oxo-2,3-dihydro-benzooxazol-6-yl,        3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,        1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,        2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, or        1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl;        wherein in a sub-embodiment, Ar¹ especially is a phenyl group of        the structure (Ar-I) (wherein in particular R^(m1) especially is        different from hydrogen), or a 5-membered heteroaryl group of        the structure (Ar-II), as defined herein above.

12) Another embodiment relates to compounds according to any one ofembodiments 8) to 10), wherein Ar¹ represents

-   -   a phenyl group of the structure (Ar-I):

-   -   wherein        -   R^(p) represents            -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein                said (C₄₋₆)cycloalkyl containing a ring oxygen atom is                unsubstituted or mono-substituted with hydroxy                (especially 3-hydroxy-oxetan-3-yl);            -   hydroxy;            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene-* (especially —NH—CH₂*,                    —NH—CH(CH₃)—*), —S—CH₂*, —CF₂—, —CH═CH—,                    ethen-1,1-diyl, or —NH—CO—*; wherein the asterisks                    indicate the bond that is linked to the —CO—R^(O1)                    group; and                -   R^(O1) represents                -    -OH;                -    -O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -    —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH,                —CH═CH—COOH, —NH—CO—COOH,];

-   -   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;            -   —CO—NR^(N3)R^(N4) wherein R^(N3) and R^(N4)                independently represent hydrogen, or (C₁₋₄)alkyl                (wherein preferably at least one of R^(N3) and R^(N4)                represents hydrogen; and wherein particular examples of                such group —CO—NR^(N3)R^(N4) are —CO—NH₂, —CO—NH(CH₃),                or —CO—NH(C₂H₅),);            -   HET¹, wherein wherein HET¹ represents                5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or                3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing                its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl); or            -   HET, wherein wherein HET represents a 5-membered                heteroaryl selected from oxazolyl, isoxazolyl,                oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,                imidazolyl, pyrazolyl, triazolyl, and tetrazolyl,                wherein said 5-membered heteroaryl is unsubstituted, or                mono-substituted, wherein the substituent is                independently selected from (C₁₋₄)alkyl (especially                methyl), (C₁₋₄)alkoxy (especially methoxy), —COOH,                hydroxy, hydroxy-(C₁₋₃)alkyl (especially hydroxymethyl),                (C₃₋₅)cycloalkyl optionally containing one ring oxygen                atom (especially cyclopropyl, oxetan-3-yl), or                —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently                represent hydrogen, (C₁₋₃)alkyl (especially methyl), or                hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);                (especially such group HET is 1H-tetrazol-5-yl,                3-hydroxy-isoxazol-5-yl,                2-hydroxy-[1,3,4]oxadiazol-4-yl);

        -   R^(m1) represents            -   hydrogen;            -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl,                isopropyl, n-butyl, isobutyl);            -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,                isopropoxy, n-butoxy, isobutoxy);            -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);            -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,                trifluoromethoxy, 2,2,2-trifluoroethoxy);            -   halogen (especially fluoro or chloro);            -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,                cyclobutyl-oxy, cyclopentyl-oxy);            -   hydroxy;            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);            -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl                (especially methyl, ethyl, n-propyl, isopropyl,                isobutyl), or (C₃₋₆)cycloalkyl optionally containing one                ring oxygen atom (especially cyclobutyl, oxetan-3-yl);                wherein in a sub-embodiment, R^(m1) especially is                different from hydrogen;

        -   R^(m2) represents hydrogen, methyl, fluoro, or chloro; and

        -   R^(o1) represents hydrogen;

    -   or Ar¹ represents a 5-membered heteroaryl group of the structure        (Ar-II):

-   -   wherein        -   Y represents CH or N;        -   R⁷ represents            -   (C₄₋₆)cycloalkyl containing a ring oxygen atom, wherein                said (C₄₋₆)cycloalkyl containing a ring oxygen atom is                unsubstituted or mono-substituted with hydroxy                (especially 3-hydroxy-oxetan-3-yl);            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene* (especially —NH—CH₂*,                    —NH—CH(CH₃)*), —CH═CH—, or —NH—CO—*; wherein the                    asterisks indicate the bond that is linked to the                    —CO—R^(O1) group; and                -   R^(O1) represents                -    -OH;                -    -O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -    —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₁₋₆)cycloalkyl wherein the                    (C₁₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —OOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—OOH, —O—C(CH₃)₂—OOH, —O—CH₂—CH₂—OOH,                —NH—CH₂—OOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CH₂—OOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—OOH,                —CH═CH—OOH, —NH—CO—COOH,];

-   -   -   -   2-hydroxy-3,4-dioxo-cyclobut-1-enyl;            -   —CO—NR^(N3)R^(N4) wherein R^(N3) and R^(N4)                independently represent hydrogen, or (C₁₋₄)alkyl                (wherein preferably at least one of R^(N3) and R^(N4)                represents hydrogen; and wherein particular examples of                such group —CO—NR^(N3)R^(N4) are —CO—NH₂, —CO—NH(CH₃),                —CO—NH(C₂H₅));            -   HET¹, wherein HET¹ represents                5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or                3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing                its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl;            -   HET, wherein wherein HET represents a 5-membered                heteroaryl selected from oxazolyl, isoxazolyl,                oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,                imidazolyl, pyrazolyl, triazolyl, and tetrazolyl,                wherein said 5-membered heteroaryl is unsubstituted, or                mono-substituted, wherein the substituent is                independently selected from (C₁₋₄)alkyl (especially                methyl), (C₁₋₄)alkoxy (especially methoxy), —COOH,                hydroxy, hydroxy-(C₁₋₃)alkyl (especially hydroxymethyl),                (C₃₋₅)cycloalkyl optionally containing one ring oxygen                atom (especially cyclopropyl, oxetan-3-yl), or                —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently                represent hydrogen, (C₁₋₃)alkyl (especially methyl), or                hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl);                (especially such group HET is 1H-tetrazol-5-yl,                3-hydroxy-isoxazol-5-yl,                2-hydroxy-[1,3,4]oxadiazol-4-yl);

        -   R⁶ represents            -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl,                isopropyl, n-butyl, isobutyl);            -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,                isopropoxy, n-butoxy);            -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);            -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,                trifluoromethoxy, 2,2,2-trifluoroethoxy);            -   halogen (especially fluoro or chloro);            -   hydroxy;            -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,                cyclobutyl-oxy, cyclopentyl-oxy);            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy);            -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl                (especially methyl, ethyl, n-propyl, isopropyl,                isobutyl), or (C₃₋₆)cycloalkyl optionally containing one                ring oxygen atom (especially cyclobutyl, oxetan-3-yl);

    -   or Ar¹ represents 8- to 10-membered bicyclic heteroaryl selected        from indazolyl, benzoimidazolyl, indolyl, benzofuranyl,        benzooxazolyl, quinoxalinyl, isoquinolinyl, or quinolinyl);        wherein said 8- to 10-membered bicyclic heteroaryl independently        is mono-substituted with —(C₀₋₃)alkylene-COOR^(O2) wherein        R^(O2) represents hydrogen or (C₁₋₄)alkyl (especially methyl)        (wherein especially such group —(C₀₋₃)alkylene-COOR^(O2) is        —COOH); (in particular such 8- to 10-membered bicyclic        heteroaryl is 3-carboxy-1H-indol-6-yl, 4-carboxy-1H-indol-2-yl,        5-carboxy-1H-indol-2-yl, 6-carboxy-1H-indol-2-yl,        7-carboxy-1H-indol-2-yl, 5-(methoxycarbonyl)-1H-indol-2-yl,        6-(methoxycarbonyl)-1H-indol-2-yl), 6-carboxy-benzofuran-2-yl,        3-carboxy-benzofuran-6-yl, 2-carboxy-benzofuran-5-yl, or        2-carboxy-benzofuran-6-yl);

    -   or Ar¹ represents a group of the structure (Ar-III):

-   -   which is selected from 2-oxo-2,3-dihydro-benzooxazol-6-yl,        3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,        1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,        2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,        1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,        1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and        1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl (in particular such        group (Ar-III) is 1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl);        wherein in a sub-embodiment, Ar¹ especially is a phenyl group of        the structure (Ar-I) (wherein in particular R^(m1) especially is        different from hydrogen), or a 5-membered heteroaryl group of        the structure (Ar-II), as defined herein above.

13) Another embodiment relates to compounds according to any one ofembodiments 8) to 10), wherein Ar represents a group selected from:

A)

or, in addition, Ar¹ represents a group selected from:B)

wherein the above groups A) and B) each form a particularsub-embodiment;wherein in a further sub-embodiment, Ar¹ especially is a phenyl group(in particular a di-substituted phenyl group), or a thiophenyl group, ora thiazolyl group, as defined in groups A) and/or B) herein above.

14) Another embodiment relates to compounds according to any one ofembodiments 8) to 10), wherein

(i) Ar¹ represents a phenyl group selected from:

(ii) or Ar¹ represents a thiophenyl group selected from:

(iii) or Ar¹ represents a thiazolyl group selected from:

(iv) or Ar¹ represents 9- or 10-membered bicyclic heteroaryl selectedfrom

(v) or Ar¹ represents a group selected from:

wherein in a sub-embodiment, Ar¹ especially is a phenyl group (inparticular a di-substituted phenyl group), or a thiophenyl group, or athiazolyl group, as defined herein above.

15) Another embodiment relates to compounds according to any one ofembodiments 8) to 10), wherein

(i) Ar¹ represents a phenyl group selected from:

-   -   a)

-   -   b)

-   -   c)

-   -   d)

(ii) or Ar¹ represents a thiophenyl group selected from:

-   -   a)

-   -   b)

-   -   c)

-   -   d)

-   -   e)

(iii) or Ar¹ represents a thiazolyl group selected from:

-   -   a)

-   -   b)

(iv) or Ar¹ represents 9- or 10-membered bicyclic heteroaryl selectedfrom

-   -   a)

-   -   b)

(v) or Ar¹ represents a group selected from:

wherein in a sub-embodiment, Ar¹ especially is a phenyl group (inparticular a di-substituted phenyl group), or a thiophenyl group, or athiazolyl group, as defined herein above.

16) Another embodiment relates to compounds according to any one ofembodiments 8) to 10), wherein Ar¹ represents a group selected from

A)

or, in addition, Ar¹ represents a group selected from:B)

wherein the above groups A) and B) each form a particularsub-embodiment.

17) Another embodiment relates to compounds according to any one ofembodiments 8) to 16), wherein in the fragment

-   -   ring (A) represents an aromatic 5- or 6-membered ring fused to        the phenyl group, wherein said ring (A) optionally contains one        or two heteroatoms independently selected from nitrogen, oxygen,        and sulfur (notably such fused group is benzofuranyl,        benzothiophenyl, benzothiazolyl, benzoisothiazolyl, indolyl,        indazolyl, naphthyl, quinolinyl, isoquinolinyl); wherein said        fragment is optionally substituted with (R¹)_(n); wherein        (R¹)_(n) represents one, two, three, or four optional        substituents (i.e. said fragment is unsubstituted, or        substituted with one, two, three, or four R¹), wherein said        substituents R¹ are independently selected from (C₁₋₃)alkyl        (especially methyl), (C₂₋₃)alkenyl (especially vinyl),        (C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy (especially        methoxy, ethoxy, isopropoxy), halogen (especially fluoro, or        chloro), (C₁₋₃)fluoroalkyl (especially trifluoromethyl),        (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy,        difluoromethoxy), cyano, or —NR^(N7)R^(N8) wherein R^(N7) and        R^(N8) independently represent hydrogen or (C₁₋₄)alkyl        (especially methyl);    -   or ring (A) represents a non-aromatic 5- to 7-membered ring        fused to the phenyl group, wherein said ring (A) optionally        contains one or two heteroatoms independently selected from        nitrogen, oxygen, and sulfur (notably such fused group is        2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,        1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,        5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,        chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,        1,2,3,4-tetrahydro-quinolinyl,        3,4-dihydro-2H-benzo[b][1,4]dioxepinyl); wherein said fragment        is optionally substituted with (R¹)_(n); wherein (R¹)_(n)        represents one, two, three, or four optional substituents (i.e.        said fragment is unsubstituted, or substituted with one, two,        three, or four R¹), wherein said substituents R¹ are        independently selected from (C₁₋₃)alkyl (especially methyl),        (C₁₋₃)alkoxy (especially methoxy, ethoxy, isopropoxy), halogen        (especially fluoro, or chloro), —S—(C₁₋₃)alkyl (especially        methylsulfanyl), (C₁₋₃)fluoroalkyl (especially trifluoromethyl),        (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy,        difluoromethoxy), cyano, or oxo.

18) Another embodiment relates to compounds according to any one ofembodiments 8) to 16), wherein the fragment

represents

-   -   a group selected from benzofuranyl, benzothiophenyl,        benzothiazolyl, benzoisothiazolyl, indolyl, indazolyl, naphthyl,        quinolinyl, and isoquinolinyl; which group independently is        unsubstituted or substituted with (R¹)_(n); wherein (R¹)_(n)        represents one, two, three, or four substituents, wherein said        substituents R¹ are independently selected from (C₁₋₃)alkyl        (especially methyl), (C₂₋₃)alkenyl (especially vinyl),        (C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy (especially        methoxy, ethoxy, isopropoxy), halogen (especially fluoro, or        chloro), —S—(C₁₋₃)alkyl (especially methylsulfanyl),        (C₁₋₃)fluoroalkyl (especially trifluoromethyl),        (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy,        difluoromethoxy), cyano, or —NR^(N7)R^(N8) wherein R^(N7) and        R^(N8) independently represent hydrogen or (C₁₋₄)alkyl        (especially methyl); [notably said substituents R¹ are        independently selected from (C₁₋₃)alkyl (especially methyl),        (C₂₋₃)alkenyl (especially vinyl), (C₂₋₃)alkynyl (especially        ethynyl), (C₁₋₃)alkoxy (especially methoxy, ethoxy, isopropoxy),        halogen (especially fluoro, or chloro), (C₁₋₃)fluoroalkyl        (especially trifluoromethyl), (C₁₋₃)fluoroalkoxy (especially        trifluoromethoxy, difluoromethoxy), cyano, or —NR^(N7)R^(N8)        wherein R^(N7) and R^(N8) independently represent hydrogen or        (C₁₋₄)alkyl (especially methyl)]; or    -   a group selected from 2,3-dihydro-benzo[b]thiophenyl,        benzo[1,3]dioxolyl, 1,3-dihydro-isobenzofuranyl,        2,3-dihydro-benzofuranyl, indanyl,        5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,        chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,        1,2,3,4-tetrahydro-quinolinyl, and        3,4-dihydro-2H-benzo[b][1,4]dioxepinyl; which group        independently is unsubstituted, or substituted with (R¹)_(n);        wherein (R¹)_(n) represents one, two, or three substituents,        wherein said substituents R¹ are independently selected from        (C₁₋₃)alkyl (especially methyl), (C₂₋₃)alkenyl (especially        vinyl), (C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy        (especially methoxy, ethoxy, isopropoxy), halogen (especially        fluoro, or chloro), —S—(C₁₋₃)alkyl (especially methylsulfanyl),        (C₁₋₃)fluoroalkyl (especially trifluoromethyl),        (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy,        difluoromethoxy), cyano, oxo, or —NR^(N7)R^(N8) wherein R^(N7)        and R^(N8) independently represent hydrogen or (C₁₋₄)alkyl        (especially methyl); [notably said substituents R¹ are        independently selected from (C₁₋₃)alkyl (especially methyl),        (C₁₋₃)alkoxy (especially methoxy, ethoxy, isopropoxy), halogen        (especially fluoro, or chloro), —S—(C₁₋₃)alkyl (especially        methylsulfanyl), (C₁₋₃)fluoroalkyl (especially trifluoromethyl),        (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy,        difluoromethoxy), cyano, or oxo].

19) Another embodiment relates to compounds according to any one ofembodiments 8) to 16), wherein the fragment

represents a group selected from the following groups a), b), c), andd):

-   -   a) benzothiophen-5-yl, benzothiophen-6-yl,        6-methyl-benzothiophen-5-yl, 3-methyl-benzothiophen-5-yl,        4-methyl-benzothiophen-5-yl, 6-methoxy-benzothiophen-5-yl,        5-methoxy-benzothiophen-6-yl, 6-cyano-benzothiophen-5-yl,        3-cyano-benzothiophen-5-yl, 6-ethoxy-benzothiophen-5-yl,        4-fluoro-7-methoxy-2-methyl-benzothiophen-6-yl,        benzoisothiazol-5-yl, benzothiazol-5-yl, benzothiazol-6-yl,        benzofuran-5-yl, benzofuran-6-yl, 6-fluoro-benzofuran-5-yl,        6-methoxy-benzofuran-5-yl, 5-methoxy-benzofuran-6-yl,        2-fluoro-5-methoxy-benzofuran-6-yl,        6-methoxy-4-methyl-benzofuran-5-yl,        4,5-difluoro-7-methoxy-2-methyl-benzofuran-6-yl,        benzooxazol-6-yl, 1H-indol-5-yl, 1H-indol-6-yl,        1-methyl-1H-indol-6-yl, 1-methyl-1H-indol-5-yl,        6-fluoro-1-methyl-1H-indol-5-yl, 1,3-dimethyl-1H-indol-5-yl,        1-ethyl-1H-indol-6-yl, or 5-methoxy-1-methyl-1H-indazol-6-yl;    -   b) naphthalen-2-yl, 3-chloro-naphthalen-2-yl,        1-chloro-naphthalen-2-yl, 8-fluoro-naphthalen-2-yl,        1-fluoro-naphthalen-2-yl, 3-methyl-naphthalen-2-yl,        1-methyl-naphthalen-2-yl, 1-amino-naphthalen-2-yl,        3-ethynyl-naphthalen-2-yl, 1-ethynyl-naphthalen-2-yl,        1-vinyl-naphthalen-2-yl, 1,3-difluoro-naphthalen-2-yl,        3-methoxy-naphthalen-2-yl, 3-cyano-naphthalen-2-yl,        1-cyano-naphthalen-2-yl, 3-methylamino-naphthalen-2-yl,        1-fluoro-3-methoxy-naphthalen-2-yl,        4-chloro-3-methoxy-naphthalen-2-yl,        4-fluoro-3-methoxy-naphthalen-2-yl, 3-ethoxy-naphthalen-2-yl,        3-methoxy-1-methyl-naphthalen-2-yl,        3-cyano-1-fluoro-naphthalen-2-yl,        3-cyano-1-methyl-naphthalen-2-yl, 3-isopropoxy-naphthalen-2-yl,        or 3-difluoromethoxy-naphthalen-2-yl;    -   c) quinolin-6-yl, 6-fluoro-isoquinolin-7-yl,        7-fluoro-isoquinolin-6-yl, 5-fluoro-quinolin-6-yl,        7-methyl-quinolin-6-yl, 8-methyl-quinolin-7-yl,        4-chloro-7-methyl-quinolin-6-yl,        7-chloro-8-methyl-quinolin-6-yl, 5,8-difluoro-quinolin-6-yl, or        7-chloro-8-fluoro-quinolin-6-yl, 5,7-difluoro-quinolin-6-yl; and    -   d) 2,3-dihydro-benzo[b]thiophen-5-yl, benzo[1,3]dioxol-5-yl,        6-methoxy-benzo[1,3]dioxol-5-yl, 6-cyano-benzo[1,3]dioxol-5-yl,        6-chloro-2,2-difluoro-benzo[1,3]dioxol-5-yl,        6-difluoromethoxy-benzo[1,3]dioxo-5-yl,        1,3-dihydro-isobenzofuran-5-yl, 2,3-dihydro-benzofuran-5-yl,        2,3-dihydro-benzofuran-6-yl, indan-5-yl,        3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl,        2,3-dihydro-benzo[1,4]dioxin-6-yl,        8-chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl,        8-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl,        8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl, chroman-7-yl,        chroman-6-yl, 6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl,        7-fluoro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,        7-fluoro-1-methyl-1,2,3,4-tetrahydro-quinolin-6-yl,        7-methoxy-1,2,3,4-tetrahydro-quinolin-6-yl,        7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl, or        8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl;        or said fragment represents a group selected from the following        groups e), f) and g):    -   e) 7-methyl-benzothiophen-5-yl, 7-methyl-benzothiophen-6-yl,        4-fluoro-benzothiophen-5-yl, 7-fluoro-benzothiophen-5-yl,        7-chloro-benzothiophen-5-yl, 3-chloro-benzothiophen-5-yl,        3-chloro-7-fluoro-benzothiophen-5-yl,        7-fluoro-6-methoxy-benzothiophen-5-yl,        7-trifluoromethyl-benzothiophen-5-yl;    -   f) 3-ethoxy-1-fluoro-naphthalen-2-yl,        3-ethoxy-1-methyl-naphthalen-2-yl; and    -   g) 7-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl,        5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,        5-fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl;        wherein the above groups a) to d), and, respectively, the above        groups e) to g) form a particular sub-embodiment.

20) Another embodiment relates to compounds according to any one ofembodiments 8) to 16), wherein the fragment

representsrepresents a group selected from the following groups a), b), c), andd):

-   -   a) benzothiophen-5-yl, 6-methyl-benzothiophen-5-yl,        4-methyl-benzothiophen-5-yl, 6-methoxy-benzothiophen-5-yl,        5-methoxy-benzothiophen-6-yl, 3-cyano-benzothiophen-5-yl,        6-ethoxy-benzothiophen-5-yl, benzothiazol-5-yl, benzofuran-5-yl,        6-fluoro-benzofuran-5-yl, 6-methoxy-benzofuran-5-yl,        5-methoxy-benzofuran-6-yl, 6-methoxy-4-methyl-benzofuran-5-yl,        1H-indol-5-yl, or 1H-indol-6-yl;    -   b) 1-methyl-naphthalen-2-yl, 1-ethynyl-naphthalen-2-yl,        3-methoxy-naphthalen-2-yl, 1-fluoro-3-methoxy-naphthalen-2-yl,        3-ethoxy-naphthalen-2-yl, 3-methoxy-1-methyl-naphthalen-2-yl, or        3-cyano-1-methyl-naphthalen-2-yl;    -   c) 7-chloro-8-fluoro-quinolin-6-yl, or        5,7-difluoro-quinolin-6-yl; and    -   d) 2,3-dihydro-benzo[b]thiophen-5-yl, benzo[1,3]dioxol-5-yl,        6-methoxy-benzo[1,3]dioxol-5-yl, 6-cyano-benzo[1,3]dioxol-5-yl,        6-difluoromethoxy-benzo[1,3]dioxol-5-yl,        7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl, or        7-fluoro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl.        or said fragment represents a group selected from the following        groups e) and f):    -   e) 7-methyl-benzothiophen-6-yl, 4-fluoro-benzothiophen-5-yl,        7-chloro-benzothiophen-5-yl, or        7-fluoro-6-methoxy-benzothiophen-5-yl; and    -   f) 7-ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,        7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl, or        7-difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl;        wherein the above groups a) to d), and, respectively, the above        groups e) and f) form a particular sub-embodiment.

21) The invention, thus, relates to compounds of the formula (I) asdefined in embodiment 1) for use according to embodiment 1), or to suchcompounds further limited by the characteristics of any one ofembodiments 2) to 20), under consideration of their respectivedependencies; to pharmaceutically acceptable salts thereof; and to theuse of such compounds according to embodiment 1), and as furtherdescribed herein below. For avoidance of any doubt, especially thefollowing embodiments relating to the compounds of formula (I) are thuspossible and intended and herewith specifically disclosed inindividualized form:

-   -   1, 2+1, 12+1, 12+2+1, 15+1, 15+2+1, 16+1, 16+2+1, 19+1, 19+2+1,        19+15+1, 19+15+2+1, 19+16+1, 19+16+2+1, 20+1, 20+2+1, 20+15+1,        20+15+2+1, 20+16+1, 20+16+2+1

In the list above the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “20+16+2+1” forexample refers to embodiment 20) depending on embodiment 16), dependingon embodiment 2), depending on embodiment 1), i.e. embodiment“20+16+2+1” corresponds to the compounds of formula (I) as defined inembodiment 1) for use according to embodiment 1), further limited by allthe structural features of the embodiments 2), 16), and 20).

22) The invention, thus, further relates to compounds of the formula(II) as defined in embodiment 8), or to such compounds further limitedby the characteristics of any one of embodiments 9) to 20), underconsideration of their respective dependencies; to pharmaceuticallyacceptable salts thereof; and to the use of such compounds asmedicaments especially in the prevention/prophylaxis or treatment ofdiseases which respond to the blockage of the EP2 receptors and/or theEP4 receptors as described herein below. For avoidance of any doubt,especially the following embodiments relating to the compounds offormula (II) are thus possible and intended and herewith specificallydisclosed in individualized form:

-   -   8, 9+8, 11+8, 11+9+8, 12+8, 12+9+8, 13+8, 13+9+8, 14+8, 14+9+8,        15+8, 15+9+8, 16+8, 16+9+8, 17+8, 17+9+8, 17+11+8, 17+11+9+8,        17+12+8, 17+12+9+8, 17+13+8, 17+13+9+8, 17+14+8, 17+14+9+8,        18+8, 18+9+8, 18+11+8, 18+11+9+8, 18+12+8, 18+12+9+8, 18+13+8,        18+13+9+8, 18+14+8, 18+14+9+8, 19+8, 19+9+8, 19+15+8, 19+15+9+8,        19+16+8, 19+16+9+8, 20+8, 20+9+8, 20+15+8, 20+15+9+8, 20+16+8,        20+16+9+8.

In the list above the numbers refer to the embodiments according totheir numbering provided hereinabove whereas “+” indicates thedependency from another embodiment. The different individualizedembodiments are separated by commas. In other words, “20+16+9+8” forexample refers to embodiment 20) depending on embodiment 16), dependingon embodiment 9), depending on embodiment 8), i.e. embodiment“20+16+9+8” corresponds to the compounds of formula (II) according toembodiment 8) further limited by all the features of the embodiments 9),16), and 20).

23) A third aspect of the invention relates to compounds of the formula(III)

wherein in compounds of the formula (III) the fragment

represents

-   -   a group selected from benzofuranyl, benzothiophenyl,        benzothiazolyl, benzoisothiazolyl, indolyl, indazolyl, naphthyl,        quinolinyl, and isoquinolinyl; which group independently is        unsubstituted or substituted with (R¹)_(n); wherein (R¹)_(n)        represents one, two, three, or four substituents, wherein said        substituents R¹ are independently selected from (C₁₋₃)alkyl        (especially methyl), (C₂₋₃)alkenyl (especially vinyl),        (C₂₋₃)alkynyl (especially ethynyl), (C₁₋₃)alkoxy (especially        methoxy, ethoxy, isopropoxy), halogen (especially fluoro, or        chloro), (C₁₋₃)fluoroalkyl (especially trifluoromethyl),        (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy,        difluoromethoxy), cyano, or —NR^(N7)R^(N8) wherein R^(N7) and        R^(N8) independently represent hydrogen or (C₁₋₄)alkyl        (especially methyl); or    -   a group selected from 2,3-dihydro-benzo[b]thiophenyl,        benzo[1,3]dioxolyl, 1,3-dihydro-isobenzofuranyl,        2,3-dihydro-benzofuranyl, indanyl,        5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,        chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,        1,2,3,4-tetrahydro-quinolinyl, and        3,4-dihydro-2H-benzo[b][1,4]dioxepinyl; which group        independently is unsubstituted, or substituted with (R¹)_(n);        wherein (R¹)_(n) represents one, two, or three substituents,        wherein said substituents R¹ are independently selected from        (C₁₋₃)alkyl (especially methyl), (C₁₋₃)alkoxy (especially        methoxy, ethoxy, isopropoxy), halogen (especially fluoro, or        chloro), —S—(C₁₋₃)alkyl (especially methylsulfanyl),        (C₁₋₃)fluoroalkyl (especially trifluoromethyl),        (C₁₋₃)fluoroalkoxy (especially trifluoromethoxy,        difluoromethoxy), cyano, or oxo;        and Ar¹ represents    -   a phenyl group of the structure (Ar-I):

-   -   wherein        -   R^(p) represents            -   X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene* (especially —NH—CH₂*,                    —NH—CH(CH₃)—*), —CH═CH—, —NH—CO—*, or                    (C₃₋₅)cycloalkylene; wherein the asterisks indicate                    the bond that is linked to the —CO—R^(O1) group; and                -   R^(O1) represents                -    -OH;                -    -O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -    —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CH₂—COOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—COOH,                —CH═CH—COOH, —NH—CO—COOH, 1-carboxy-cyclopropan-1-yl];            -   HET¹, wherein HET¹ represents                5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or                3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing                its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl); or            -   HET, wherein HET represents a 5-membered heteroaryl                selected from oxazolyl, isoxazolyl, oxadiazolyl,                thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl,                pyrazolyl, triazolyl, or tetrazolyl; in particular                isoxazolyl, oxadiazolyl and tetrazolyl, wherein said                5-membered heteroaryl is unsubstituted, or                mono-substituted with —COOH, hydroxy,                hydroxy-(C₁₋₃)alkyl (especially hydroxymethyl), or                —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently                represent hydrogen, (C₁₋₃)alkyl (especially methyl), or                hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl); [in                particular HET is unsubstituted or mono-substituted with                hydroxy; especially HET is 1H-tetrazol-5-yl,                3-hydroxy-isoxazol-5-yl, or                2-hydroxy-[1,3,4]oxadiazol-4-yl];        -   R^(m1) represents            -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl,                isopropyl, n-butyl, isobutyl);            -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,                isopropoxy, n-butoxy, isobutoxy);            -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);            -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,                trifluoromethoxy, 2,2,2-trifluoroethoxy);            -   halogen (especially fluoro or chloro);            -   (C₃₋₆)cycloalkyl (especially cyclopropyl);            -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,                cyclobutyl-oxy, cyclopentyl-oxy);            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy); or            -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl                (especially methyl, ethyl, n-propyl, isopropyl,                isobutyl), or (C₃₋₆)cycloalkyl optionally containing one                ring oxygen atom (especially cyclobutyl, oxetan-3-yl);        -   R^(m2) represents hydrogen, methyl, fluoro, or chloro; and        -   R^(o1) represents hydrogen;    -   or Ar¹ represents a 5-membered heteroaryl group of the structure        (Ar-II):

-   -   wherein        -   Y represents CH or N;        -   R⁷ represents            -   —X¹—CO—R^(O1), wherein                -   X¹ represents a direct bond, (C₁₋₃)alkylene                    (especially —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂—CH₂—),                    —O—(C₁₋₃)alkylene-* (especially —O—CH₂—*,                    —O—CH(CH₃)—*, —O—C(CH₃)₂—*, —O—CH₂—CH₂—*),                    —NH—(C₁₋₃)alkylene* (especially —NH—CH₂*,                    —NH—CH(CH₃)—*), —S—CH₂*, —CF₂—, —CH═CH—, —CH≡CH—,                    —NH—CO—*, —CO—, or (C₃₋₅)cycloalkylene; wherein the                    asterisks indicate the bond that is linked to the                    —CO—R^(O1) group; and                -   R^(O1) represents                -    -OH;                -    -O—(C₁₋₄)alkyl (especially ethoxy, methoxy);                -    —NH—SO₂—R^(S3) wherein R^(S3) represents                    (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the                    (C₃₋₆)cycloalkyl optionally contains a ring oxygen                    atom, (C₁₋₃)fluoroalkyl, or —NH₂;            -   [wherein in particular such group —X¹—CO—R^(O1)                represents —COOH, —CO—O—CH₃, —CO—O—C₂H₅, —O—CH₂—COOH,                —O—CH(CH₃)—COOH, —O—C(CH₃)₂—COOH, —O—CH₂—CH₂—COOH,                —NH—CH₂—COOH, —NH—CH₂—CO—O—CH₃, —NH—CH(CH₃)—COOH,                —CO—NH—SO₂—CH₃, —CO—NH—SO₂—C(CH₃)₂,                —CO—NH—SO₂-cyclopropyl, —CO—NH—SO₂—C₂H₅, —CO—NH—SO₂—NH₂,                —CH₂—OOH, —CH₂—CO—O—CH₃, —CH₂—CO—O—C₂H₅, —CH₂—CH₂—OOH,                —CH═CH—OOH, —NH—CO—OOH, 1-carboxy-cyclopropan-1-yl];            -   HET¹, wherein HET¹ represents                5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl (encompassing                its tautomeric form 5-hydroxy-[1,2,4]oxadiazol-3-yl), or                3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl (encompassing                its tautomeric form 3-hydroxy-[1,2,4]oxadiazol-5-yl); or            -   HET, wherein HET represents a 5-membered heteroaryl                selected from oxazolyl, isoxazolyl, oxadiazolyl,                thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl,                pyrazolyl, triazolyl, or tetrazolyl; in particular                isoxazolyl, oxadiazolyl and tetrazolyl, wherein said                5-membered heteroaryl is unsubstituted, or                mono-substituted with —COOH, hydroxy,                hydroxy-(C₁₋₃)alkyl (especially hydroxymethyl), or                —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independently                represent hydrogen, (C₁₋₃)alkyl (especially methyl), or                hydroxy-(C₂₋₄)alkyl (especially 2-hydroxy-ethyl); [in                particular HET is unsubstituted or mono-substituted with                hydroxy; especially HET is 1H-tetrazol-5-yl,                3-hydroxy-isoxazol-5-yl, or                2-hydroxy-[1,3,4]oxadiazol-4-yl];        -   R⁶ represents            -   (C₁₋₆)alkyl (especially methyl, ethyl, n-propyl,                isopropyl, n-butyl, isobutyl);            -   (C₁₋₄)alkoxy (especially methoxy, ethoxy, n-propoxy,                isopropoxy, n-butoxy);            -   (C₁₋₃)fluoroalkyl (especially trifluoromethyl);            -   (C₁₋₃)fluoroalkoxy (especially difluoromethoxy,                trifluoromethoxy, 2,2,2-trifluoroethoxy);            -   halogen (especially fluoro or chloro);            -   (C₃₋₆)cycloalkyl (especially cyclopropyl);            -   (C₃₋₆)cycloalkyl-oxy (especially cyclopropyl-oxy,                cyclobutyl-oxy, cyclopentyl-oxy);            -   hydroxy-(C₂₋₄)alkoxy (especially 2-hydroxy-ethoxy); or            -   —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl                (especially methyl, ethyl, n-propyl, isopropyl,                isobutyl), or (C₃₋₆)cycloalkyl optionally containing one                ring oxygen atom (especially cyclobutyl, oxetan-3-yl).

24) Another embodiment relates to compounds of formula (I) as defined inembodiment 1) for use according to embodiment 1) which are selected fromthe following compounds:

-   [2-(5,7-Difluoro-quinolin-6-yl)-ethyl]-(6-quinolin-6-yl-pyrimidin-4-yl)-amine;-   [2-(1H-Indol-6-yl)-ethyl]-[6-(1H-indol-5-yl)-pyrimidin-4-yl]-amine;-   [2-(1H-Indol-6-yl)-ethyl]-[6-(1H-indol-6-yl)-pyrimidin-4-yl]-amine;-   5-{6-[2-(1H-Indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid amide;-   [2-(5,7-Difluoro-quinolin-6-yl)-ethyl]-(6-isoquinolin-6-yl-pyrimidin-4-yl)-amine;    and-   [2-(5,7-Difluoro-quinolin-6-yl)-ethyl]-[6-(1H-indol-5-yl)-pyrimidin-4-yl]-amine.

25) Another embodiment relates to compounds of formula (II) according toembodiment 8), which are selected from the following compounds:

-   3-Ethoxy-5-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic-   acid;-   3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzo[b]thiophen-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(5-methoxy-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(2,3-Dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   3-Ethoxy-5-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   2-Cyclobutoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-Ethoxy-5-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic    acid;-   4-{6-[2-(1-Fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   3-Ethoxy-5-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(8-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-benzofuran-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1-methyl-1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(5,7-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(3-Difluoromethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(3-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-(2-Hydroxy-ethoxy)-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(6-ethoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   5-[6-(2-Chroman-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   3-(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-propionic    acid;-   4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   5-{6-[2-(6-Cyano-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(2,3-Dihydro-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   2-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Fluoro-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-6-propyl-benzoic    acid;-   4-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   6-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzofuran-2-carboxylic    acid;-   2-Difluoromethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   6-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-benzofuran-2-carboxylic    acid;-   5-{6-[2-(7-Chloro-8-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzothiazol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzofuran-2-carboxylic    acid;-   5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-2-methyl-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   2-Cyclobutoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   (2-Ethoxy-4-{6-[2-(3-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   3-Ethoxy-5-{6-[2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   2-Ethoxy-4-{6-[2-(3-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethylsulfanyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   5-[6-(2-Benzo[1,3]dioxol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   (2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   5-{6-[2-(7-Chloro-8-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   (2-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   5-{6-[2-(6-Difluoromethoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   (2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   2-Cyclobutoxy-4-{6-[2-(5-methoxy-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoic    acid;-   2-Ethoxy-4-{6-[2-(6-ethoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-4-carboxylic    acid;-   4-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic    acid;-   4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoic    acid;-   5-[6-(2-Benzo[d]isothiazol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   4-{6-[2-(2,3-Dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   5-[6-(2-Benzooxazol-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   (3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic    acid;-   2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(5-Methoxy-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   2-Ethylsulfanyl-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(5-methoxy-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   (2-Ethoxy-4-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   5-{6-[2-(1,3-Dihydro-isobenzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   2-Butoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(2,3-dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   5-{6-[2-(4-Chloro-7-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   3-(3-Ethoxy-5-{6-[2-(1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(5-(6-((2-(1H-indol-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol];-   3-{5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(5-(6-((2-(benzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(6-methoxybenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(5-(6-((2-(1H-indol-6-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol];-   3-{5-[6-(2-Benzo[1,3]dioxol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(5-(6-((2-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol];-   3-(3-Ethoxy-5-{6-[2-(7-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(3-ethoxy-5-(6-((2-(7-fluoroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol];-   {6-[4-Ethoxy-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-pyrimidin-4-yl}-[2-(7-fluoro-quinolin-6-yl)-ethyl]-amine;-   4-Ethoxy-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylic    acid;-   3-(4-Ethoxy-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(4-ethoxy-2-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol];-   3-(4-Ethyl-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(4-ethyl-2-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol];-   3-Ethoxy-5-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)-N-sulfamoylthiophene-2-carboxamide;    and-   N-(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbonyl)-methanesulfonamide.

26) In addition to the compounds listed in embodiment 25), furthercompounds of formula (II) according to embodiment 8), are selected fromthe following compounds:

-   2-Cyclobutoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(6-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   4-{6-[2-(6-Methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   6-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzofuran-3-carboxylic    acid;-   4-{6-[2-(4-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-phenyl)-acetic    acid;-   2-Ethoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-(2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic    acid;-   4-{6-[2-(6-Fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   4-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoic    acid;-   4-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoic    acid;-   2-Ethoxy-4-{6-[2-(6-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(6-Methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid; and-   2-Ethoxy-4-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid.

27) In addition to the compounds listed in embodiments 25) and 26),further compounds of formula (II) according to embodiment 8), areselected from the following compounds:

-   3-Ethoxy-5-{6-[2-(1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-fluoro-1-methyl-1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(4-Chloro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(8-methyl-quinolin-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   5-{6-[2-(1-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-[6-(2-naphthalen-2-yl-ethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic    acid;-   (2-Ethoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   3-Ethoxy-5-{6-[2-(3-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-[6-(2-indan-5-yl-ethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic    acid;-   5-{6-[2-(8-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic    acid;-   5-{6-[2-(4,5-Difluoro-7-methoxy-2-methyl-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-[6-(2-Chroman-7-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   (2-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   5-{6-[2-(3-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(1-methyl-1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(8-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(5-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   2-Cyclobutoxy-4-{6-[2-(7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   5-{6-[2-(1-Amino-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-{6-[2-(7-Fluoro-1-methyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylic    acid;-   4-{6-[2-(3-Cyano-1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic    acid;-   3-Ethoxy-5-{6-[2-(1-vinyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   2-Isobutyl-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-Ethoxy-5-{6-[2-(7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   (4-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic    acid;-   (4-{6-[2-(3-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenoxy)-acetic    acid;-   5-{6-[2-(5,8-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   (2-Ethoxy-4-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   5-{6-[2-(1-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   5-[6-(2-Benzothiazol-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(3-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic    acid;-   3-Ethoxy-5-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(7-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-Ethoxy-5-{6-[2-(6-fluoro-isoquinolin-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   (4-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic    acid;-   5-{6-[2-(7-Fluoro-isoquinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylic    acid;-   4-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxy-benzoic    acid;-   5-{6-[2-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   (4-{6-[2-(1-Fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-phenyl)-acetic    acid;-   {4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxy}-acetic    acid;-   (2-Ethoxy-4-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-acetic    acid;-   2-Ethoxy-4-{6-[2-(4-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   5-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   3-{3-Ethoxy-5-[6-(2-quinolin-6-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(3-ethoxy-5-(6-((2-(quinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol];    and-   3-{3-Ethoxy-5-[6-(2-naphthalen-2-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(3-ethoxy-5-(6-((2-(naphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol]. 27)    In addition to the compounds listed in embodiments 25) and 26),    further compounds of formula (II) according to embodiment 8), are    selected from the following compounds:-   5-{6-[2-(7-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   4-{6-[2-(7-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   2-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-Ethoxy-5-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (2-Ethoxy-6-fluoro-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethoxy-6-fluoro-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   3-Ethoxy-5-{6-[2-(7-methyl-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic    acid;-   4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic    acid;-   4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic    acid;-   4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic    acid;-   (2-Methoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-acetic    acid;-   (2-Methoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Methoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic    acid;-   3-Ethoxy-5-{6-[2-(7-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   (4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-phenyl)-acetic    acid;-   (4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-phenyl)-acetic    acid;-   2-Ethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (4-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (2-Ethoxy-6-fluoro-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   4-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-6-fluoro-phenyl)-acetic    acid;-   2-Ethoxy-4-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   2-Cyclobutoxy-4-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (4-{6-[2-(5-Fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-phenyl)-acetic    acid;-   (2-Isobutyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-phenyl)-acetic    acid;-   4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoic    acid;-   4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoic    acid;-   4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoic    acid;-   2-Ethoxy-4-{6-[2-(3-ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(3-Ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (2-Ethoxy-4-{6-[2-(3-ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   3-(2-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic    acid;-   3-(2-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic    acid;-   (4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropoxy-phenyl)-acetic    acid;-   (2-Isopropoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic    acid;-   (4-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic    acid;-   4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxy-benzoic    acid;-   (4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic    acid;-   2-Isopropoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   5-{6-[2-(7-Difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic    acid;-   (2-Methoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   2-Ethoxy-4-{6-[2-(5-fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(3-ethoxy-1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenoxy)-propionic    acid;-   2-Ethoxy-4-{6-[2-(7-ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (4-{6-[2-(7-Ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (2-Difluoromethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Difluoromethoxy-4-{6-[2-(5-fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Difluoromethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethyl-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethyl-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   2-Ethyl-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclopropoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclopropoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclopropoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic    acid;-   3-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5(4H)-one    [tautomeric form:    3-(2-ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5-ol];-   {6-[3-Ethoxy-4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethyl]-amine;-   4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutoxy-benzoic    acid;-   (3-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic    acid;-   4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzamide;-   4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic    acid;-   3-Ethoxy-5-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxyli    acid;-   (4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-acetic    acid;-   (4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   2-(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-propionic    acid;-   4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic    acid;-   4-{6-[2-(7-Difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic    acid;-   (4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic    acid;-   (4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic    acid;-   (4-{6-[2-(7-Ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-acetic    acid;-   (4-{6-[2-(5-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (2-Difluoromethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   2-Ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclopropoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclopropoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (3-Difluoromethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic    acid;-   and-   3-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazole-5(4H)-thione-   [tautomeric form:    3-(2-ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazole-5-thiol].

28) In addition to the compounds listed in embodiments 25), 26) and 27),further compounds of formula (II) according to embodiment 8), areselected from the following compounds:

-   (4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-phenyl)-acetic    acid;-   2-Butoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Ethoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   (4-{6-[2-(5-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic    acid;-   (4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethyl-phenyl)-acetic    acid;-   2-Ethyl-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethyl-benzoic    acid;-   2-Cyclopropoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid; and-   (4-{6-[2-(7-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid. 29) In addition to the compounds listed in embodiments 25),    26), 27) and 28), further compounds of formula (II) according to    embodiment 8), are selected from the following compounds:-   (4-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic    acid;-   (2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethoxy-6-fluoro-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethoxy-6-fluoro-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-acetic    acid;-   (4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-phenyl)-acetic    acid;-   4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoic    acid;-   2-Isobutyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic    acid;-   (4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropoxy-phenyl)-acetic    acid;-   3-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenoxy)-propionic    acid;-   3-Ethyl-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-N-(2-hydroxy-ethyl)-benzamide;-   (4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-acetic    acid;-   2-{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-propyl-phenyl}-propionic    acid;-   2-(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-propionic    acid;-   3-Ethoxy-5-{6-[2-(7-trifluoromethyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic    acid;-   3-(4-(6-((2-(7-Fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-[1,2,4]oxadiazol-5(4H)-one-   [tautomeric form:    3-(4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5-ol];-   7-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1-methyl-3,4-dihydro-1H-quinazolin-2-one;-   4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2,6-dimethyl-phenol;-   2-Ethylsulfanyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   2-Cyclobutoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid;-   3-(3-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-propionic    acid;-   3-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-4-hydroxy-cyclobut-3-ene-1,2-dione;-   (2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-oxo-acetic    acid;-   2-Cyclopropoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic    acid methyl ester;-   (2-Chloro-6-ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic    acid;-   (2-Ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-6-methyl-phenyl)-acetic    acid;-   (3-Ethyl-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic    acid;-   5-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-isoxazol-3-ol    [tautomeric form:    5-(2-ethoxy-4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)phenyl)    isoxazol-3(2H)-one];-   5-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-isoxazol-3-ol-   [tautomeric form:    5-(4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)-2-methoxyphenyl)    isoxazol-3(2H)-one]; and-   (5-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-propyl-thiophen-2-yl)-acetic    acid.

The compounds of formula (I)/formula (II) according to embodiments 1) to29) and their pharmaceutically acceptable salts can be used asmedicaments, e.g. in the form of pharmaceutical compositions for enteral(such especially oral e.g. in form of a tablet or a capsule) orparenteral administration (including topical application or inhalation).

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the described compounds of formula(I)/formula (II) or their pharmaceutically acceptable salts, optionallyin combination with other therapeutically valuable substances, into agalenical administration form together with suitable, non-toxic, inert,therapeutically compatible solid or liquid carrier materials and, ifdesired, usual pharmaceutical adjuvants.

The present invention also relates to a method for theprevention/prophylaxis or treatment of a disease or disorder mentionedherein comprising administering to a subject a pharmaceutically activeamount of a compound of formula (I)/formula (II) according toembodiments 1) to 29).

In a preferred embodiment of the invention, the administered amount iscomprised between 1 mg and 2000 mg per day, particularly between 5 mgand 1000 mg per day, more particularly between 25 mg and 500 mg per day,especially between 50 mg and 200 mg per day.

Whenever the word “between” is used to describe a numerical range, it isto be understood that the end points of the indicated range areexplicitly included in the range. For example: if a temperature range isdescribed to be between 40° C. and 80° C., this means that the endpoints 40° C. and 80° C. are included in the range; or if a variable isdefined as being an integer between 1 and 4, this means that thevariable is the integer 1, 2, 3, or 4.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C., andpreferably to an interval extending from Y minus 5° C. to Y plus 5° C.

For avoidance of any doubt, if compounds are described as useful for theprevention/prophylaxis or treatment of certain diseases, such compoundsare likewise suitable for use in the preparation of a medicament for theprevention/prophylaxis or treatment of said diseases. Likewise, suchcompounds are also suitable in a method for the prevention/prophylaxisor treatment of such diseases, comprising administering to a subject(mammal, especially human) in need thereof, an effective amount of suchcompound.

The compounds of formula (I)/formula (II) according to embodiments 1) to29) are useful for the prevention/prophylaxis or treatment of disordersrelating to the EP2 and/or EP4 receptors.

Certain compounds of formula (I)/formula (II) according toembodiments 1) to 29) exhibit their biological activity as modulators ofthe prostaglandin 2 receptors EP2 and/or EP4 in a biologicalenvironment, (i.e. in the presence of one or more enzymes capable ofbreaking a covalent bond linked to a carbonyl group such as an amidase,an esterase or any suitable equivalent thereof capable of removing aprodrug group from a carboxylic acid group.

Diseases or disorders relating to the EP2 and/or EP4 receptors areespecially

-   -   cancer (notably melanoma including metastatic melanoma; lung        cancer including non-small cell lung cancer; bladder cancer        including urinary bladder cancer, urothelial cell carcinoma;        renal carcinomas including renal cell carcinoma, metastatic        renal cell carcinoma, metastatic renal clear cell carcinoma;        gastro-intestinal cancers including colorectal cancer,        metastatic colorectal cancer, familial adenomatous polyposis        (FAP), oesophageal cancer, gastric cancer, gallbladder cancer,        cholangiocarcinoma, hepatocellular carcinoma, and pancreatic        cancer such as pancreatic adenocarcinoma or pancreatic ductal        carcinoma; endometrial cancer; ovarian cancer; cervical cancer;        neuroblastoma; prostate cancer including castrate-resistant        prostate cancer; brain tumors including brain metastases,        malignant gliomas, glioblastoma multiforme, medulloblastoma,        meningiomas; breast cancer including triple negative breast        carcinoma; oral tumors; nasopharyngeal tumors; thoracic cancer;        head and neck cancer; leukemias including acute myeloid        leukemia, adult T-cell leukemia; carcinomas; adenocarcinomas;        thyroid carcinoma including papillary thyroid carcinoma;        choriocarcinoma; Ewing's sarcoma; osteosarcoma;        rhabdomyosarcoma; Kaposi's sarcoma; lymphoma including Burkitt's        lymphoma, Hodgkin's lymphoma, MALT lymphoma; multiple myelomas;        and virally induced tumors; especially melanoma; lung cancer;        bladder cancer; renal carcinomas; gastro-intestinal cancers;        endometrial cancer; ovarian cancer; cervical cancer; and        neuroblastoma);        as well as further diseases or disorders relating to the EP2        and/or EP4 receptors such as:    -   pain (notably inflammatory pain and painful menstruation);    -   endometriosis;    -   autosomal dominant polycystic kidney disease;    -   acute ischemic syndromes in atherosclerotic patients;    -   pneumonia; and    -   neurodegenerative diseases including amyotrophic lateral        sclerosis, stroke; Parkinson disease, Alzheimer's disease and        HIV associated dementia;    -   and EP2 and/or EP4 antagonists may further be used to control        female fertility.

The compounds of formula (I)/formula (II) according to any one ofembodiments 1) to 29) are in particular useful as therapeutic agents forthe prevention/prophylaxis or treatment of a cancer. They can be used assingle therapeutic agents or in combination with one or morechemotherapy agents and/or radiotherapy and/or targeted therapy. Suchcombined treatment may be effected simultaneously, separately, or over aperiod of time.

The invention, thus, also relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier material, and:

-   -   a compound of formula (I)/formula (II) according to any one of        embodiments 1) to 29);    -   and one or more cytotoxic chemotherapy agents.

The invention, thus, further relates to a kit comprising

-   -   a pharmaceutical composition, said composition comprising a        pharmaceutically acceptable carrier material, and:        -   a compound of formula (I)/formula (II) according to any one            of embodiments 1) to 29);    -   and instructions how to use said pharmaceutical composition for        the prevention/prophylaxis or the treatment of a cancer, in        combination with chemotherapy and/or radiotherapy and/or        targeted therapy.

The terms “radiotherapy” or “radiation therapy” or “radiation oncology”,refer to the medical use of ionizing radiation in theprevention/prophylaxis (adjuvant therapy) and/or treatment of cancer;including external and internal radiotherapy.

The term “targeted therapy” refers to the prevention/prophylaxis(adjuvant therapy) and/or treatment of cancer with one or moreanti-neoplastic agents such as small molecules or antibodies which acton specific types of cancer cells or stromal cells. Some targetedtherapies block the action of certain enzymes, proteins, or othermolecules involved in the growth and spread of cancer cells. Other typesof targeted therapies help the immune system kill cancer cells(immunotherapies); or inhibit angiogenesis, the growth and formation ofnew blood vessels in the tumor; or deliver toxic substances directly tocancer cells and kill them. An example of a targeted therapy which is inparticular suitable to be combined with the compounds of the presentinvention is immunotherapy, especially immunotherapy targeting theprogrammed cell death receptor 1 (PD-1 receptor) or its ligand PD-L1(Zelenay et al., 2015, Cell 162, 1-14; Yongkui Li et al., Oncoimmunology2016, 5(2):e1074374).

When used in combination with the compounds of formula (I)/formula (II),the term “targeted therapy” especially refers to agents such as:

-   -   a) Epidermal growth factor receptor (EGFR) inhibitors or        blocking antibodies (for example Gefitinib, Erlotinib, Afatinib,        Icotinib, Lapatinib, Panitumumab, Zalutumumab, Nimotuzumab,        Matuzumab and Cetuximab);    -   b) RAS/RAF/MEK pathway inhibitors (for example Vemurafenib,        Sorafenib, Dabrafenib, GDC-0879, PLX-4720, LGX818, RG7304,        Trametinib (GSK1120212), Cobimetinib (GDC-0973/XL518),        Binimetinib (MEK162, ARRY-162), Selumetinib (AZD6244));    -   c) Aromatase inhibitors (for example Exemestane, Letrozole,        Anastrozole, Vorozole, Formestane, Fadrozole);    -   d) Angiogenesis inhibitors, especially VEGF signalling        inhibitors such as Bevacuzimab (Avastin), Ramucirumab, Sorafenib        or Axitinib;    -   e) Immune Checkpoint inhibitors (for example: anti-PD1        antibodies such as Pembrolizumab (Lambrolizumab, MK-3475),        Nivolumab, Pidilizumab (CT-011), AMP-514/MED10680, PDR001,        SHR-1210; REGN2810, BGBA317; fusion proteins targeting PD-1 such        as AMP-224; small molecule anti-PD1 agents such as for example        compounds disclosed in WO2015/033299, WO2015/044900 and        WO2015/034820; anti-PD1L antibodies, such as BMS-936559,        atezolizumab (MPDL3280A, RG7446), MED14736, avelumab        (MSB0010718C), durvalumab (MED14736); anti-PDL2 antibodies, such        as AMP224; anti-CTLA-4 antibodies, such as ipilimumab,        tremilmumab; anti-Lymphocyte-activation gene 3 (LAG-3)        antibodies, such as BMS-986016, IMP701, MK-4280, ImmuFact        IMP321; anti T cell immunoglobulin mucin-3 (TIM-3) antibodies,        such as MBG453; anti-CD137/4-1BB antibodies, such as        BMS-663513/urelumab, PF-05082566; anti T cell immunoreceptor        with Ig and ITIM domains (TIGIT) antibodies, such as RG6058        (anti-TIGIT, MTIG7192A);    -   f) Vaccination approaches (for example dendritic cell        vaccination, peptide or protein vaccination (for example with        gp100 peptide or MAGE-A3 peptide);    -   g) Re-introduction of patient derived or allogenic (non-self)        cancer cells genetically modified to secrete immunomodulatory        factors such as granulocyte monocyte colony stimulating factor        (GMCSF) gene-transfected tumor cell vaccine (GVAX) or        Fms-related tyrosine kinase 3 (Flt-3) ligand gene-transfected        tumor cell vaccine (FVAX), or Toll like receptor enhanced GM-CSF        tumor based vaccine (TEGVAX);    -   h) T-cell based adoptive immunotherapies, including chimeric        antigen receptor (CAR) engineered T-cells (for example CTL019);    -   i) Cytokine or immunocytokine based therapy (for example        Interferon alpha, interferon beta, interferon gamma, interleukin        2, interleukin 15);    -   j) Toll-like receptor (TLR) agonists (for example resiquimod,        imiquimod, glucopyranosyl lipid A, CpG oligodesoxynucleotides);    -   k) Thalidomide analogues (for example Lenalidomide,        Pomalidomide);    -   l) Indoleamin-2,3-Dioxgenase (IDO) and/or        Tryptophane-2,3-Dioxygenase (TDO) inhibitors (for example        RG6078/NLG919/GDC-0919; Indoximod/1MT (1-methyltryptophan),        INCB024360/Epacadostat, PF-06840003 (EOS200271), F001287);    -   m) Activators of T-cell co-stimulatory receptors (for example        anti-OX40/CD134 (Tumor necrosis factor receptor superfamily,        member 4, such as RG7888 (MOXR0916), 9B12; MED6469, GSK3174998,        MED0562), anti OX40-Ligand/CD252; anti-glucocorticoid-induced        TNFR family related gene (GITR) (such as TRX518, MED11873,        MK-4166, BMS-986156), anti-CD40 (TNF receptor superfamily        member 5) antibodies (such as Dacetuzumab (SGN-40), HCD122,        CP-870,893, RG7876, ADC-1013, APX005M, SEA-CD40);        anti-CD40-Ligand antibodies (such as BG9588); anti-CD27        antibodies such as Varlilumab);    -   n) Molecules binding a tumor specific antigen as well as a        T-cell surface marker such as bispecific antibodies (for example        RG7802 targeting CEA and CD3) or antibody fragments, antibody        mimetic proteins such as designed ankyrin repeat proteins        (DARPINS), bispecific T-cell engager (BITE, for example AMG103,        AMG330);    -   o) Antibodies or small molecular weight inhibitors targeting        colony-stimulating factor-1 receptor (CSF-1R) (for example        Emactuzumab (RG7155), Cabiralizumab (FPA-008), PLX3397);    -   p) Agents targeting immune cell check points on natural killer        cells such as antibodies against Killer-cell immunoglobulin-like        receptors (KIR) for example Lirilumab (IPH2102/BMS-986015);    -   q) Agents targeting the Adenosine receptors or the ectonucleases        CD39 and CD73 that convert ATP to Adenosine, such as MED19447        (anti-CD73 antibody), PBF-509; CPI-444 (Adenosine A2a receptor        antagonist).

When used in combination with the compounds of formula (I)/formula (II),immune checkpoint inhibitors such as those listed under d), andespecially those targeting the programmed cell death receptor 1 (PD-1receptor) or its ligand PD-L1, are preferred.

The term “chemotherapy” refers to the treatment of cancer with one ormore cytotoxic anti-neoplastic agents (“cytotoxic chemotherapy agents”).Chemotherapy is often used in conjunction with other cancer treatments,such as radiation therapy or surgery. The term especially refers toconventional cytotoxic chemotherapeutic agents which act by killingcells that divide rapidly, one of the main properties of most cancercells. Chemotherapy may use one drug at a time (single-agentchemotherapy) or several drugs at once (combination chemotherapy orpolychemotherapy). Chemotherapy using drugs that convert to cytotoxicactivity only upon light exposure is called photochemotherapy orphotodynamic therapy.

The term “cytotoxic chemotherapy agent” or “chemotherapy agent” as usedherein refers to an active anti-neoplastic agent inducing apoptosis ornecrotic cell death. When used in combination with the compounds offormula (I)/formula (II), the term especially refers to conventionalcytotoxic chemotherapy agents such as:

-   -   a) alkylating agents (for example mechlorethamine, chlorambucil,        cyclophosphamide, ifosfamide, streptozocin, carmustine,        lomustine, melphalan, dacarbazine, temozolomide, fotemustine,        thiotepa or altretamine; especially cyclophosphamide,        carmustine, melphalan, dacarbazine, or temozolomide);    -   b) platinum drugs (especially cisplatin, carboplatin or        oxaliplatin);    -   c) antimetabolite drugs (for example 5-fluorouracil, folic        acid/leucovorin, capecitabine, 6-mercaptopurine, methotrexate,        gemcitabine, cytarabine, fludarabine or pemetrexed; especially        5-fluorouracil, folic acid/leucovorin, capecitabine,        methotrexate, gemcitabine or pemetrexed);    -   d) anti-tumor antibiotics (for example daunorubicin,        doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin,        mitomycin-C or mitoxantrone; especially doxorubicin);    -   e) mitotic inhibitors (for example paclitaxel, docetaxel,        ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or        estramustine; especially paclitaxel, docetaxel, ixabepilone or,        vincristine); or    -   f) topoisomerase inhibitors (for example etoposide, teniposide,        topotecan, irinotecan, diflomotecan or elomotecan; especially        etoposide or irinotecan).

When used in combination with the compounds of formula (I)/formula (II),preferred cytotoxic chemotherapy agents are the above-mentionedalkylating agents (notably fotemustine, cyclophosphamide, ifosfamide,carmustine, dacarbazine and prodrugs thereof such as especiallytemozolomide or pharmaceutically acceptable salts of these compounds; inparticular temozolomide); mitotic inhibitors (notably paclitaxel,docetaxel, ixabepilone; or pharmaceutically acceptable salts of thesecompounds; in particular paclitaxel); platinum drugs (notably cisplatin,oxaliplatin and carboplatin); as well etoposide and gemcitabine.

Chemotherapy may be given with a curative intent or it may aim toprolong life or to palliate symptoms.

-   -   Combined modality chemotherapy is the use of drugs with other        cancer treatments, such as radiation therapy or surgery.    -   Induction chemotherapy is the first line treatment of cancer        with a chemotherapeutic drug. This type of chemotherapy is used        for curative intent.    -   Consolidation chemotherapy is the given after remission in order        to prolong the overall disease free time and improve overall        survival. The drug that is administered is the same as the drug        that achieved remission.    -   Intensification chemotherapy is identical to consolidation        chemotherapy but a different drug than the induction        chemotherapy is used.    -   Combination chemotherapy involves treating a patient with a        number of different drugs simultaneously. The drugs differ in        their mechanism and side effects. The biggest advantage is        minimising the chances of resistance developing to any one        agent. Also, the drugs can often be used at lower doses,        reducing toxicity.    -   Neoadjuvant chemotherapy is given prior to a local treatment        such as surgery, and is designed to shrink the primary tumor. It        is also given to cancers with a high risk of micrometastatic        disease.    -   Adjuvant chemotherapy is given after a local treatment        (radiotherapy or surgery). It can be used when there is little        evidence of cancer present, but there is risk of recurrence. It        is also useful in killing any cancerous cells that have spread        to other parts of the body. These micrometastases can be treated        with adjuvant chemotherapy and can reduce relapse rates caused        by these disseminated cells.    -   Maintenance chemotherapy is a repeated low-dose treatment to        prolong remission.    -   Salvage chemotherapy or palliative chemotherapy is given without        curative intent, but simply to decrease tumor load and increase        life expectancy. For these regimens, a better toxicity profile        is generally expected.

“Simultaneously”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat approximately the same time; wherein it is understood that asimultaneous administration will lead to exposure of the subject to thetwo or more active ingredients and/or treatments at the same time. Whenadministered simultaneously, said two or more active ingredients may beadministered in a fixed dose combination, or in an equivalent non-fixeddose combination (e.g. by using two or more different pharmaceuticalcompositions to be administered by the same route of administration atapproximately the same time), or by a non-fixed dose combination usingtwo or more different routes of administration; wherein saidadministration leads to essentially simultaneous exposure of the subjectto the two or more active ingredients and/or treatments. For example,when used in combination with chemotherapy and/or suitable targetedtherapy, the present EP2/EP4 antagonists would possibly be used“simultaneously”.

“Fixed dose combination”, when referring to an administration type,means in the present application that the administration type concernedconsists in the administration of one single pharmaceutical compositioncomprising the two or more active ingredients.

“Separately”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat different points in time; wherein it is understood that a separateadministration will lead to a treatment phase (e.g. at least 1 hour,notably at least 6 hours, especially at least 12 hours) where thesubject is exposed to the two or more active ingredients and/ortreatments at the same time; but a separate administration may also leadto a treatment phase where for a certain period of time (e.g. at least12 hours, especially at least one day) the subject is exposed to onlyone of the two or more active ingredients and/or treatments. Separateadministration especially refers to situations wherein at least one ofthe active ingredients and/or treatments is given with a periodicitysubstantially different from daily (such as once or twice daily)administration (e.g. wherein one active ingredient and/or treatment isgiven e.g. once or twice a day, and another is given e.g. every otherday, or once a week or at even longer distances). For example, when usedin combination with radiotherapy, the present EP2/EP4 antagonists wouldpossibly be used “separately”.

By administration “over a period of time” is meant in the presentapplication the subsequent administration of two or more activeingredients and/or treatments at different times. The term in particularrefers to an administration method according to which the entireadministration of one of the active ingredients and/or treatments iscompleted before the administration of the other/the others begins. Inthis way it is possible to administer one of the active ingredientsand/or treatments for several months before administering the otheractive ingredient(s) and/or treatment(s).

Administration “over a period of time” also encompasses situationswherein the compound of formula (I)/formula (II) would be used in atreatment that starts after termination of an initial chemotherapeutic(for example an induction chemotherapy) and/or radiotherapeutictreatment and/or targeted therapy treatment, wherein optionally saidtreatment would be in combination with a further/an ongoingchemotherapeutic and/or radiotherapeutic treatment and/or targetedtherapy treatment (for example in combination with a consolidationchemotherapy, an intensification chemotherapy, an adjuvant chemotherapy,or a maintenance chemotherapy; or radiotherapeutic equivalents thereof);wherein such further/ongoing chemotherapeutic and/or radiotherapeutictreatment and/or targeted therapy treatment would be simultaneously,separately, or over a period of time in the sense of “not given with thesame periodicity”.

The compounds of formula (I)/formula (II) as defined in embodiments 1)to 29) are also useful in a method of modulating an immune response in asubject having a tumor, comprising the administration of an effectiveamount of the compound of formula (I)/formula (II) [wherein notably saidadministration of said effective amount results in the pharmacologicallyactive blockage of the EP2 receptors, or of the EP4 receptors, or ofboth the EP2 and the EP4 receptors]; wherein said effective amountreactivates the immune system in the tumor of said subject; whereinespecially said effective amount:

-   -   counteracts the polarization of tumor-associated macrophages        towards tumor-promoting M2 macrophages; and/or    -   down-regulates the activation, expansion and/or the effector        function of immunosuppressive cells that have accumulated in a        tumor (especially of regulatory T cells (Tregs) and/or myeloid        derived suppressor cells (MDSC)); and/or    -   up-regulates IFN-γ and/or TNF-α and/or IL-12 and/or IL-2        expression in immune cells such as natural killer cells,        T-cells, dendritic cells and macrophages (leading to the        induction of tumor cell apoptosis and/or restrained        tumorigenesis); and/or    -   directly or indirectly counteracts the suppressed activation,        IL-2 responsiveness and expansion of cytotoxic T-cells (thereby        decreasing local immunsuppression).

The compounds of formula (I)/formula (II) as defined in embodiments 1)to 29) are also useful in a method of diminishing tumor growth and/orreducing tumor size in a subject having a tumor, comprising theadministration of an effective amount of the compound of formula(I)/formula (II) [wherein notably said administration of said effectiveamount results in the pharmacologically active blockage of the EP2receptors, or of the EP4 receptors, or of both the EP2 and the EP4receptors]; wherein said effective amount down-regulates tumorangiogenesis (especially by decreasing endothelial cell motility and/orsurvival, and/or by decreasing the expression of VEGF (vascularendothelial growth factor)); and/or wherein said effective amountdiminishes tumor cell survival and/or induces tumor cell apoptosis(especially via inhibition of P3K/AKT and MAPK signalling).

The compounds of formula (I)/formula (II) as defined in embodiments 1)to 29) are also useful in a method of modulating an immune response in asubject having a tumor, comprising the administration of an effectiveamount of the compound of formula (I)/formula (II) [wherein notably saidadministration of said effective amount results in the pharmacologicallyactive blockage of the EP2 receptors, or of the EP4 receptors, or ofboth the EP2 and the EP4 receptors]; wherein said effective amountreactivates the immune system in the tumor of said subject; wherein saideffective amount activates the cytotoxicity and cytokine production ofnatural killer cells and/or cytotoxic T-cells.

Besides, any preferences and (sub-)embodiments indicated for thecompounds of formula (II) (whether for the compounds themselves, saltsthereof, compositions containing the compounds or salts thereof, or usesof the compounds or salts thereof, etc.) apply mutatis mutandis tocompounds of formula (I).

Preparation of Compounds of Formula (I)/Formula (II):

The compounds of formula (I)/formula (II) can be prepared by well-knownliterature methods, by the methods given below, by the methods given inthe experimental part below or by analogous methods. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by a person skilled in the art byroutine optimisation procedures. In some cases the order of carrying outthe following reaction schemes, and/or reaction steps, may be varied tofacilitate the reaction or to avoid unwanted reaction products. In thegeneral sequence of reactions outlined below, the generic groups R¹, R³,R^(4a), R^(4b), R^(5a), R^(5b) and Ar¹ are as defined for formula(I)/formula (II). Other abbreviations used herein are explicitlydefined, or are as defined in the experimental section. In someinstances the generic groups R¹, R³, R^(4a), R^(4b), R^(5a), R^(5b) andAr¹ might be incompatible with the assembly illustrated in the schemesbelow and so will require the use of protecting groups (PG). The use ofprotecting groups is well known in the art (see for example “ProtectiveGroups in Organic Synthesis”, T. W. Greene, P. G. M. Wuts,Wiley-Interscience, 1999). For the purposes of this discussion, it willbe assumed that such protecting groups as necessary are in place. Insome cases the final product may be further modified, for example, bymanipulation of substituents to give a new final product. Thesemanipulations may include, but are not limited to, reduction, oxidation,alkylation, acylation, hydrolysis and transition-metal catalysedcross-coupling reactions which are commonly known to those skilled inthe art. The compounds obtained may also be converted into salts,especially pharmaceutically acceptable salts, in a manner known per se.

Compounds of formula (I)/formula (II) of the present invention can beprepared according to the general sequence of reactions outlined below.

A general synthetic route allowing the preparation of compounds offormula (I)/formula (II) is presented in scheme 1. Thus, precursors A3can be obtained by nucleophilic aromatic substitutions between primaryamines A1 and pyrimidines A2 (wherein X is a chlorine, a bromine or aniodine), in the presence of a base such as TEA, DIPEA or K₂CO₃, in asolvent such as isopropanol, butanol, DMF or THF, at RT or at elevatedtemperatures. Compounds of formula (I) can be produced via Suzukicross-coupling reactions of the pyrimidine halide derivatives A3 withboronic acids or boronate esters A4. Typical Suzuki cross-couplingreactions may be carried out in the presence of a base such as K₂CO₃,Cs₂CO₃, Na₂CO₃, K₃PO₄, or CsF and a catalyst such as Pd(PPhs)₄,Pd(dppf)Cl₂ or Pd(OAc)₂, in a solvent like ethanol, THF, water, ormixtures thereof, typically at elevated temperatures. Boronic acids orboronate esters A4 can be obtained from commercial sources, orsynthesized by methods described in the literature, or by methods knownby a person skilled in the art. A boronic acid derivative can be formedby the Miyaura borylation reaction, by cross-coupling ofbis(pinacolato)diboron with aryl halides or triflates, in the presenceof a base such as potassium acetate and a catalyst such as Pd(dppf)Cl₂.Alternatively, a boronic acid derivative can be formed by alithiation/borylation sequence, typically at low temperatures, usingbutyllithium or lithium diisopropylamide as the base, andtri-isopropylborate or isopropoxyboronic acid pinacol ester, in asolvent such as diethyl ether or THF. In a variant, compounds of formula(I) can be prepared via nucleophilic aromatic substitutions betweenprimary amines A1 and substituted pyrimidine halides A5, wherein X is achlorine, a bromine or an iodine (scheme 1).

Alternatively, compounds of formula (I) can be synthesized by reacting acompound of formula A1 with a compound of formula A5 wherein Xrepresents OH, in presence of a coupling agent such as(benzotriazol-1-yloxy)-tris(dimethylamino)-phosphoniumhexafluorophosphate (BOP),(benzotriazol-1-yl-oxy)-tripyrrolidino-phosphonium hexafluorophosphate(PyBOP) or hexachlorocyclotriphosphazene, in presence of a base such asDBU, DIPEA or TEA in a solvent such as THF, MeCN or DMF, at lowtemperatures, or at RT or at elevated temperatures.

Preparations of the required primary amines A1 are described in scheme2. Aminoethylated aromatics or heteroaromatics B3 can be produced viaSuzuki-Miyaura cross-coupling reactions of the corresponding aromatic orheteroaromatic electrophiles B1 (bromides, iodides or triflates) withBoc-protected potassium R-aminoethyltrifluoroborates B2. Suchcross-coupling reactions can be performed using described conditions[Pd(dppf)Cl₂ or combination of Pd(OAc)₂ and RuPhos as the catalyticsystem, Cs₂CO₃ as a base, in a mixture of toluene/H₂O, at elevatedtemperatures]. The corresponding primary amines A1 can be obtained afterBoc-deprotection of derivatives B3, under acidic conditions, and can beconverted into compounds of formula (I) with the synthetic sequencesdescribed in scheme 1. In a variant presented in scheme 2, primaryamines A1 can be prepared starting from carbonyl precursors B4 and nitrocompounds B5 via Henry reaction (butylamine/acetic acid/molecularsieves/90° C.) and subsequent reduction of the produced nitroalkenes B6(lithium aluminum hydride/THF/80° C.).

The specific preparation of β-aminoethyl aromatics/heteroaromatics C9possessing two ortho-substituents (R^(1a) and R^(1b)) is described inscheme 3. Derivatives C9 can be synthesized with a directed-metalationbased approach by using the methoxymethyl (MOM) moiety as anortho-directing group. MOM-protected derivatives (C2/C5) can be accessedfrom the corresponding hydroxy-aromatics/heteroaromatics C1 and C4(NaH/MeOCH₂Cl/DMF) and can be converted regioselectively to thecorresponding derivatives C3 via ortho-lithiation (n-BuLi/THF/−78° C.)and subsequent quenching with the appropriate electrophilic reagent. Themethoxymethyl group in C3 can be removed under mild acidic conditions togive derivatives C6 that can be converted to the corresponding triflatesC7 for subsequent coupling with Boc-protected potassiumβ-aminoethyltrifluoroborates B2. Boc-deprotection of the resultingproducts C8 can deliver the corresponding primary amines C9 that can beconverted into compounds of formula (I) according to sequences describedin scheme 1.

Substituted benzothiophenes corresponding to compounds of formula (I)can be prepared according to the synthetic route described in scheme 4.Ortho-fluorobenzaldehydes or ortho-chlorobenzaldehydes D1 can undergoaromatic nucleophilic substitution by treatment with methylthioglycolate D2 in the presence of a base (K₂CO₃/DMF), and thebenzothiophene derivatives D3 can result from a subsequent ring closureat elevated temperatures. Alkaline hydrolysis of the ester functionalityin D3 followed by copper-mediated decarboxylation of the resultingbenzothiophene-2-carboxylic acids (CuO/DMF/140° C.) can providederivatives 4. A subsequent Suzuki-Miyaura aminoethylation ofbromobenzothiophenes D4 using Boc-protected potassium3-aminoethyltrifluoroborates B2 can furnish derivatives D5 that can beconverted to primary amines D6 after Boc-deprotection under acidicconditions. Finally, target products D7 corresponding to compounds offormula (I) can be obtained with the sequences described in scheme 1.

Substituted benzofurans corresponding to compounds of formula (I) can beprepared according to the synthetic route shown in scheme 5.Ortho-hydroxybenzaldehydes E1 can be converted to the correspondingphenoxyacetic acids E3 via O-alkylation with ethyl bromoacetate E2followed by saponification of the ester functionality. Subsequentheating of the resulting carboxylic acids E3 with sodium acetate inacetic anhydride can deliver the substituted benzofurans E4.Suzuki-Miyaura aminoethylation of bromobenzofurans E4 usingBoc-protected potassium β-aminoethyltrifluoroborates B2 can then furnishderivatives E5 that can be converted to primary amines E6 afterBoc-deprotection under acidic conditions. Target products E7corresponding to compounds of formula (I) can be finally obtained fromE6 with the preparations described in scheme 1.

The following examples are provided to illustrate the invention. Theseexamples are illustrative only and should not be construed as limitingthe invention in any way.

EXPERIMENTAL PART

I. Chemistry

All temperatures are stated in ° C. Commercially available startingmaterials were used as received without further purification. Unlessotherwise specified, all reactions were carried out in oven-driedglassware under an atmosphere of nitrogen. Compounds were purified byflash column chromatography on silica gel or by preparative HPLC.Compounds described in the invention are characterised by LC-MS data(retention time t_(R) is given in min; molecular weight obtained fromthe mass spectrum is given in g/mol) using the conditions listed below.In cases where compounds of the present invention appear as a mixture ofconformational isomers, particularly visible in their LC-MS spectra, theretention time of the most abundant conformer is given. In some casescompounds are isolated after purification in form of the correspondingammonium salt (*1), or the respective formic acid salt (*2); suchcompounds are marked accordingly.

Analytical LC-MS Equipment:

-   -   HPLC pump: Binary gradient pump, Agilent G4220A or equivalent    -   Autosampler: Gilson LH215 (with Gilson 845z injector) or        equivalent    -   Column compartment: Dionex TCC-3000RS or equivalent    -   Degasser: Dionex SRD-3200 or equivalent    -   Make-up pump: Dionex HPG-3200SD or equivalent    -   DAD detector: Agilent G4212A or equivalent    -   MS detector: Single quadrupole mass analyzer, Thermo Finnigan        MSQPlus or equivalent    -   ELS detector: Sedere SEDEX 90 or equivalent        LC-MS with Acidic Conditions    -   Method A: Column: Zorbax SB-aq (3.5 μm, 4.6×50 mm). Conditions:        MeCN [eluent A]; water+0.04% TFA [eluent B]. Gradient: 95% B→5%        B over 1.5 min (flow: 4.5 mL/min). Detection: UV/Vis+MS.    -   Method B: Column: Zorbax RRHD SB-aq (1.8 μm, 2.1×50 mm).        Conditions: MeCN [eluent A]; water+0.04% TFA [eluent B].        Gradient: 95% B→5% B over 2.0 min (flow: 0.8 mL/min). Detection:        UV/Vis+MS.    -   Method C: Column: Waters XBridge C18 (2.5 μm, 4.6×30 mm).        Conditions: MeCN [eluent A]; water+0.04% TFA [eluent B].        Gradient: 95% B→5% B over 1.5 min (flow: 4.5 mL/min). Detection:        UV/Vis+MS.    -   Method D: Waters Acquity Binary, Solvent Manager, MS: Waters SQ        Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC        ELSD. Column ACQUITY UPLC CSH C18 1.7 um 2.1×50 mm from Waters,        thermostated in the Acquity UPLC Column Manager at 60° C.        Eluents: A: H₂O+0.05% formic acid; B: MeCN+0.045% formic acid.        Method: Gradient: 2% B 98% B over 2.0 min. Flow: 1.0 mL/min.        Detection: UV 214 nm and ELSD, and MS, t_(R) is given in min.        LC-MS with Basic Conditions    -   Method E: Column: Waters BEH C₁₈ (3.0×50 mm, 2.5 μm). Eluents:        A: Water/NH₃ [c(NH₃)=13 mmol/l], B: MeCN, Method: 5% B to 95% B        in 2 min, Flow 1.6 ml/min, Detection UV: 214 nm.        Preparative HPLC Equipment:    -   Gilson 333/334 HPLC pump equipped with Gilson LH215, Dionex        SRD-3200 degasser,    -   Dionex ISO-3100A make-up pump, Dionex DAD-3000 DAD detector,        Single quadrupole mass analyzer MS detector, Thermo Finnigan MSQ        Plus, MRA100-000 flow splitter, Polymer Laboratories PL-ELS1000        ELS detector        Preparative HPLC with Basic Conditions    -   Column: Waters XBridge (10 μm, 75×30 mm). Conditions: MeCN        [eluent A]; water+0.5% NH₄OH (25% aq.) [eluent B]; Gradient see        Table 1 (flow: 75 mL/min), the starting percentage of Eluent        A (x) is determined depending on the polarity of the compound to        purify. Detection: UV/Vis+MS

TABLE 1 t (min) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) x x 95 95 x x EluentB (%) 100-x 100-x  5  5 100-x 100-xPreparative HPLC with Acidic Conditions

-   -   Column: Waters Atlantis T3 (10 μm, 75×30 mm). Conditions: MeCN        [eluent A]; water+0.5% HCO₂H [eluent B]; Gradient see Table 2        (flow: 75 mL/min), the starting percentage of Eluent A (x) is        determined depending on the polarity of the compound to purify.        Detection: UV/Vis+MS

TABLE 2 t (min) 0 0.01 4.0 6.0 6.2 6.6 Eluent A (%) x x 95 95 x x EluentB (%) 100-x 100-x  5  5 100-x 100-x

Abbreviations (as Used Hereinbefore or Hereinafter)

-   -   AcOH acetic acid    -   anh. anhydrous    -   aq. aqueous    -   atm atmosphere    -   Boc tert-butoxycarbonyl    -   BOP (benzotriazol-1-yloxy)-tris(dimethylamino)-phosphonium        hexafluorophosphate    -   BuLi n-butyllithium    -   d days    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCM dichloromethane    -   DIBAL/DIBAL-H diisobutylaluminium hydride    -   DIPEA diisopropyl-ethylamine, Hünig's base    -   DMAP 4-Dimethylaminopyridine    -   DMF dimethylformamide    -   DMSO dimethylsulfoxide    -   dppf 1,1′-bis(diphenylphosphino)ferrocene    -   EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   Et ethyl    -   Et₂O diethylether    -   EtOAc ethyl acetate    -   EtOH ethanol    -   Ex. example    -   FC flash chromatography on silica gel    -   h hour(s)    -   HATU        (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid    -   hexafluorophosphate    -   hept heptane(s)    -   HCl hydrochloric acid or hydrogen chloride    -   HOBT 1-hydroxybenzotriazol    -   HPLC high performance liquid chromatography    -   H₂SO₄ sulfuric acid    -   HV high vacuum conditions    -   ^(i)Bu isobutyl    -   ^(i)Pr isopropyl    -   LAH Lithium aluminium hydride    -   LC-MS liquid chromatography-mass spectrometry    -   Lit. Literature    -   M mol/l    -   Me methyl    -   MeCN acetonitrile    -   MeOH methanol    -   MgSO₄ magnesium sulfate    -   mL milliliter    -   min minute(s)    -   MOM methoxymethyl    -   MW microwave    -   NaHCO₃ sodium hydrogencarbonate    -   NaOH sodium hydroxide    -   NMP N-methyl-2-pyrrolidone    -   ^(i)Pr n-propyl    -   OAc acetate    -   Pd(OAc)₂ palladium(II) acetate    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)    -   PdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium(II) dichloride    -   Pd(dppf)Cl₂        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   Pd(dppf)Cl₂-DCM        [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)        complex    -   with dichloromethane    -   Pd(PPhs)₄ tetrakis(triphenylphosphine)palladium(0)    -   Ph phenyl    -   PPh₃ triphenyl phosphine    -   prep. Preparative    -   PTFE polytetrafluoroethylene    -   PyBOP (benzotriazol-1-yl-oxy)-tripyrrolidino-phosphonium        hexafluorophosphate    -   rac racemic    -   RM reaction mixture    -   RT room temperature    -   RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl    -   s second(s)    -   sat. saturated (if not indicated otherwise: sat. aq.)    -   Selectfluor        1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane        bis(tetrafluoroborate)    -   tBu tert-butyl=tertiary butyl    -   TEA triethylamine    -   Tf trifluoromethanesulfonyl    -   TFA trifluoroacetic acid    -   TH F tetrahydrofuran    -   TLC thin layer chromatography    -   TMEDA N,N,N′,N′-tetramethylethylenediamine    -   tosyl p-toluene-sulfonyl    -   t_(R) retention time    -   triflate trifluoromethanesulfonate    -   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

A—Preparation of Precursors and Intermediates A.1. Synthesis ofPyrimidine Halide Derivatives of Formula (A3) A.1.1.6-Chloro-N-(2-(3-ethoxynaphthalen-2-yl)ethyl)pyrimidin-4-amine

To a solution of 2-(3-ethoxynaphthalen-2-yl)ethan-1-amine hydrochloride(560 mg, 2.16 mmol) in 2-propanol (22 mL) at RT are added TEA (1.05 mL,7.54 mmol) and 4,6-dichloropyrimidine (398 mg, 2.67 mmol). The RM isrefluxed (90° C.), under nitrogen, for 1.5 h and is then allowed to coolto RT. DCM and water are added and the layers are separated. The aq.layer is extracted twice with DCM and the combined organic layers arethen washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords6-chloro-N-(2-(3-ethoxynaphthalen-2-yl)ethyl)pyrimidin-4-amine as anoff-white solid (570 mg, 80%). LC-MS A: t_(R)=0.99 min; [M+H]⁺=328.09.

A.1.1.1. 2-(3-Ethoxynaphthalen-2-yl)ethan-1-amine hydrochloride

To a solution of tert-butyl (2-(3-ethoxynaphthalen-2-yl)ethyl)carbamate(680 mg, 2.16 mmol) in DCM (20 mL) is added 4 M HCl in dioxane (4.30 mL,17.20 mmol) and the RM is stirred overnight at RT. The RM is thenconcentrated under reduced pressure affording2-(3-ethoxynaphthalen-2-yl)ethan-1-amine hydrochloride as a pale yellowsolid (560 mg, quantitative). LC-MS A: t_(R)=0.62 min; [M+H]⁺=216.16.

A.1.1.2. Tert-butyl (2-(3-ethoxynaphthalen-2-yl)ethyl)carbamate

A mixture of 2-bromo-3-ethoxynaphthalene (682 mg, 2.66 mmol), potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (751 mg, 2.99 mmol)and cesium carbonate (2.658 g, 8.15 mmol) in toluene (15 mL) and water(5 mL) is degassed three times. Palladium(II) acetate (30.6 mg, 0.13mmol) and RuPhos (134 mg, 0.27 mmol) are then added and the mixture isheated to 95° C., under nitrogen, overnight. The RM is allowed to coolto RT. Water is added and the RM is extracted twice with EtOAc. Thecombined organic layers are then washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords tert-butyl(2-(3-ethoxynaphthalen-2-yl)ethyl)carbamate as an off-white solid (680mg, 81%). LC-MS A: t_(R)=0.99 min: [M+H]⁺=316.19.

A.1.1.3. 2-Bromo-3-ethoxynaphthalene

A solution of 3-bromonaphthalen-2-ol (600 mg, 2.66 mmol) in anh. DMF (14mL) is treated at RT with cesium carbonate (868 mg, 2.66 mmol) andiodoethane (0.235 mL, 2.92 mmol) and the RM is stirred at RT, undernitrogen, for 1.25 h. Water is added and the mixture is extracted threetimes with Et₂O. The combined organic layers are then washed twice withwater, dried over anh. MgSO₄, filtered and concentrated under reducedpressure affording 2-bromo-3-ethoxynaphthalene as a colorless solid (682mg, quantitative). LC-MS A: t_(R)=0.97 min; no ionization.

A.1.2. 6-Chloro-N-(2-(1-methylnaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1-methylnaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.94 min; [M+H]⁺=298.08.

A.1.2.1. 2-(1-Methylnaphthalen-2-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1-methylnaphthalen-2-yl)ethyl)carbamate. LC-MS A: t_(R)=0.58 min;[M+H]⁺=186.21.

A.1.2.2. Tert-butyl (2-(1-methylnaphthalen-2-yl)ethyl)carbamate

A mixture of 2-bromo-1-methylnaphthalene (1.000 g, 4.52 mmol), potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (1.147 g, 4.56mmol) and cesium carbonate (4.421 g, 13.56 mmol) in toluene (30 mL) andwater (10 mL) is degassed three times. Pd(dppf)Cl₂ (185 mg, 0.22 mmol)is then added and the mixture is heated to 95° C., under nitrogen,overnight. The RM is allowed to cool to RT. Water is added and the RM isextracted twice with EtOAc. The combined organic layers are then washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (heptane/EtOAc=7/3) affordstert-butyl (2-(1-methylnaphthalen-2-yl)ethyl)carbamate as a pale yellowsolid (933 mg, 72%). LC-MS A: t_(R)=0.97 min; no ionization.

A.1.3. 6-Chloro-N-(2-(8-fluoronaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(8-fluoronaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.03 min; [M+H]⁺=302.23.

A.1.3.1. 2-(8-Fluoronaphthalen-2-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(8-fluoronaphthalen-2-yl)ethyl)carbamate. LC-MS B: t_(R)=0.59 min;[M+H]⁺=190.22.

A.1.3.2. Tert-butyl (2-(8-fluoronaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 8-fluoronaphthalen-2-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.05 min; no ionization.

A.1.3.3. 8-Fluoronaphthalen-2-yl trifluoromethanesulfonate

A solution of 8-fluoronaphthalen-2-ol (640 mg, 3.87 mmol) and TEA (1.40mL, 10.04 mmol) in anh. DCM (38 mL) is treated portionwise at RT with1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.678 g, 4.65 mmol) and the RM is stirred at RT, under nitrogen,overnight. The RM is then concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords8-fluoronaphthalen-2-yl trifluoromethanesulfonate as a yellow oil (1.33g, quantitative). LC-MS B: t_(R)=1.09 min; no ionization.

A.1.4. 6-Chloro-N-(2-(3-methoxynaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(3-methoxynaphthalen-2-yl)ethan-1-amine. LC-MSA: t_(R)=0.94 min; [M+H]⁺=314.08.

A.1.4.1. 2-(3-Methoxynaphthalen-2-yl)ethan-1-amine

To a solution of 3-methoxy-2-naphthaldehyde (2.00 g, 10.74 mmol) innitromethane (20 mL) are added successively 4A molecular sieves (100mg), butylamine (0.126 mL, 1.27 mmol) and acetic acid (0.125 mL, 2.18mmol). The RM is heated to 90° C., under nitrogen, for 30 min. The RM isthen filtered and the filtrate is concentrated under reduced pressure.Purification by FC (heptane/DCM=1/1) affords2-methoxy-3-(2-nitrovinyl)naphthalene as a yellow solid (1.49 g, 61%).LC-MS A: t_(R)=0.95 min; no ionisation

To a cooled (0° C.) solution of 2-methoxy-3-(2-nitrovinyl)naphthalene(1.49 g, 6.49 mmol) in anh. THE (10 mL) is added dropwise a solution oflithium aluminum hydride (2 M in THF, 11.4 mL, 22.8 mmol). The mixtureis then heated at reflux (80° C.), under nitrogen, for 15 min. Thecooled (0° C.) RM is treated successively with water (0.9 mL), 15% aq.NaOH (0.9 mL), and water (2.6 mL). The resulting heterogeneous mixtureis then filtered and the separated solid is washed with Et₂O. The layersof the filtrate are separated and the aqueous layer is extracted withEt₂O. The combined organic layers are then dried over anh. MgSO₄,filtered and concentrated under reduced pressure affording2-(3-methoxynaphthalen-2-yl)ethan-1-amine as a yellow oil (1.30 g, 99%).LC-MS A: t_(R)=0.58 min; [M+H]⁺=202.20.

A.1.5. 6-Chloro-N-(2-(naphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(naphthalen-2-yl)ethan-1-amine. LC-MS A:t_(R)=0.91 min; [M+H]⁺=283.93.

A.1.5.1. 2-(Naphthalen-2-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 2-naphthaldehyde. LC-MS A: t_(R)=0.55 min;[M+H]⁺=172.12.

A.1.6. 6-Chloro-N-(2-(3-methylnaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(3-methylnaphthalen-2-yl)ethan-1-amine. LC-MS A:t_(R)=0.95 min; [M+H]⁺=298.11.

A.1.6.1. 2-(3-Methylnaphthalen-2-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 3-methyl-2-naphthaldehyde. LC-MS A: t_(R)=0.59min: [M+H]⁺=186.28.

A.1.6.2. 3-Methyl-2-naphthaldehyde

To a cooled (−78° C.) solution of 2-bromo-3-methylnaphthalene (733 mg,3.31 mmol) in anh. THE (44 mL) is added a solution of BuLi (1.6 M inhexanes, 2.10 mL, 3.36 mmol) and the RM is further stirred at −78° C.,under nitrogen, for 2 min. A solution of anh. DMF (363 mg, 4.97 mmol) inanh. THE (3 mL) is then added to the previous mixture and stirring at−78° C. is continued for 45 min. The RM is then treated dropwise withsat. aq. NH₄Cl (10 mL) and is allowed to warm-up to RT. Water (40 mL)and Et₂O (100 mL) are then added and the layers are separated. The aq.layer is further extracted with Et₂O and the combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (heptane/DCM=1/1) affords 3-methyl-2-naphthaldehydeas a colorless solid (0.42 g, 74%). LC-MS A: t_(R)=0.87 min; noionization.

A.1.7. 6-Chloro-N-(2-(1-fluoronaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1-fluoronaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.93 min; [M+H]⁺=302.04.

A.1.7.1. 2-(1-Fluoronaphthalen-2-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1-fluoronaphthalen-2-yl)ethyl)carbamate. LC-MS A: t_(R)=0.56 min;[M+H]⁺=190.16.

A.1.7.2. Tert-butyl (2-(1-fluoronaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 2-bromo-1-fluoronaphthalene. LC-MS A: t_(R)=0.95min; no ionization.

A.1.8.6-Chloro-N-(2-(3-(difluoromethoxy)naphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(3-(difluoromethoxy)naphthalen-2-yl)ethan-1-amine hydrochloride. LC-MSA: t_(R)=0.95 min; [M+H]⁺=350.11.

A.1.8.1. 2-(3-(Difluoromethoxy)naphthalen-2-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-(difluoromethoxy)naphthalen-2-yl)ethyl)carbamate. LC-MS A:t_(R)=0.63 min; [M+H]⁺=238.17.

A.1.8.2. Tert-butyl(2-(3-(difluoromethoxy)naphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 2-bromo-3-(difluoromethoxy)naphthalene. LC-MS A:t_(R)=0.97 min; no ionization.

A.1.8.3. 2-Bromo-3-(difluoromethoxy)naphthalene

To a cooled (0° C.) solution of 3-bromonaphthalen-2-ol (515 mg, 2.29mmol) in MeCN (13 mL) and water (13 mL) is added potassium hydroxide(2.56 g, 45.62 mmol). The mixture is stirred at RT for 30 min, and isthen cooled to −78° C. Diethyl (bromodifuoromethyl)phosphonate (1.24 g,4.57 mmol) is added in one portion to the cooled mixture and stirring isthen continued at RT overnight. Et₂O is added, the layers are separatedand the aqueous layer is further extracted with Et₂O. The combinedorganic layers are successively washed with 1 M aq. NaOH, water andbrine and are then dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/7) affords 2-bromo-3-(difluoromethoxy)naphthalene as apale yellow oil (432 mg, 69%). LC-MS A: t_(R)=0.95 min; no ionization.

A.1.9. 6-Chloro-N-(2-(3-chloronaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(3-chloronaphthalen-2-yl)ethan-1-amine. LC-MS A:t_(R)=0.96 min; [M+H]⁺=317.99.

A.1.9.1. 2-(3-Chloronaphthalen-2-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 3-chloro-2-naphthaldehyde. LC-MS A: t_(R)=0.60min; [M+H]⁺=206.27.

A.1.9.2. 3-Chloro-2-naphthaldehyde

To a cooled (0° C.) suspension of pyridinium chlorochromate (906 mg,4.20 mmol) in DCM (10 mL) is added a solution of(3-chloronaphthalen-2-yl)methanol (540 mg, 2.80 mmol) in DCM (25 mL).The resulting black suspension is further stirred at 0° C., undernitrogen, for 15 min and then at RT overnight. The RM is then filteredover celite and the filtrate is concentrated under reduced pressure.Purification by FC (DCM) affords 3-chloro-2-naphthaldehyde as a paleyellow solid (504 mg, 94%). LC-MS A: t_(R)=0.89 min; no ionization.

A.1.9.3. (3-Chloronaphthalen-2-yl)methanol

To a cooled (−78° C.) solution of methyl 3-chloro-2-naphthoate (660 mg,2.99 mmol) in anh. toluene (20 mL) is added dropwise a solution ofDIBAL-H (1 M in toluene, 9.0 mL, 9.0 mmol). The mixture is furtherstirred at −78° C., under nitrogen, for 15 min and is then allowed towarm-up to 0° C. Stirring at 0° C. is continued for 30 min, and thecooled RM is treated successively with water (8 mL) and with 1 N aq.NaOH (16 mL). The mixture is then allowed to warm-up to RT, EtOAc isadded and the layers are separated. The aqueous layer is extracted twicewith EtOAc. The combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressureaffording (3-chloronaphthalen-2-yl)methanol as a pale pink solid (540mg, 94%). LC-MS A: t_(R)=0.79 min; no ionization.

A.1.9.4. Methyl 3-chloro-2-naphthoate

To a solution of 3-chloro-2-naphthoic acid (770 mg, 3.18 mmol) in anh.DMF (18 mL) at RT are added cesium carbonate (1.457 g, 4.47 mmol) andiodomethane (0.469 mL, 7.46 mmol) and the RM is stirred at RT, undernitrogen, for 30 min. Water and Et₂O are added and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=7/3) affords methyl 3-chloro-2-naphthoateas an orange solid (660 mg, 94%). LC-MS A: t_(R)=0.90 min;[M+H]⁺=221.20.

A.1.9.5. 3-Chloro-2-naphthoic acid

To a cooled (0° C.) solution of 3-amino-2-naphthoic acid (700 mg, 3.18mmol) in MeCN (16 mL), water (8 mL) and 12 M aq. HCl (2.15 mL) is addeddropwise a solution of sodium nitrite (241 mg, 3.50 mmol) in water (2.5mL). The RM is further stirred at 0° C. for 1 h and a solution ofcopper(I) chloride (1.888 g, 19.10 mmol) in 2 M aq. HCl (5 mL) is thenadded dropwise to the cooled mixture. Stirring at 0° C. is continued for10 min and the mixture is then heated to 50° C. for 45 min. Theresulting RM is then allowed to cool to RT and is poured onto ice/water.The mixture is extracted three times with EtOAc and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure affording 3-chloro-2-naphthoic acidas a brown solid (770 mg, quantitative). LC-MS A: t_(R)=0.77 min; noionization.

A.1.10.6-Chloro-N-(2-(3-isopropoxynaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(3-isopropoxynaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=1.01 min; [M+H]⁺=342.16.

A.1.10.1. 2-(3-Isopropoxynaphthalen-2-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-isopropoxynaphthalen-2-yl)ethyl)carbamate. LC-MS A: t_(R)=0.68min; [M+H]⁺=230.20.

A.1.10.2. Tert-butyl (2-(3-isopropoxynaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 2-bromo-3-isopropoxynaphthalene. LC-MS A:t_(R)=1.02 min; [M+H]⁺=330.19.

A.1.10.3. 2-Bromo-3-isopropoxynaphthalene

To a solution of 3-bromonaphthalen-2-ol (600 mg, 2.66 mmol) in anh. DMF(14 mL) at RT are added cesium carbonate (954 mg, 2.93 mmol) and2-iodopropane (0.292 mL, 2.93 mmol) and the RM is heated to 60° C. for 6h. The RM is allowed to cool to RT, water and Et₂O are added and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure affording2-bromo-3-isopropoxynaphthalene as an orange oil (749 mg, quantitative).LC-MS A: t_(R)=1.00 min; no ionization.

A.1.11.6-Chloro-N-(2-(3-(methylamino)naphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 3-(2-aminoethyl)-N-methylnaphthalen-2-aminehydrochloride. LC-MS B: t_(R)=0.94 min; [M+H]⁺=313.18.

A.1.11.1. 3-(2-Aminoethyl)-N-methylnaphthalen-2-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-(methylamino)naphthalen-2-yl)ethyl)carbamate. LC-MS B: t_(R)=0.58min; [M+H]⁺=201.17.

A.1.11.2. Tert-butyl (2-(3-(methylamino)naphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 3-iodo-N-methylnaphthalen-2-amine. LC-MS B:t_(R)=0.97 min; [M+H]⁺=301.22.

A.1.11.3. 3-Iodo-N-methylnaphthalen-2-amine

To a solution of 3-iodonaphthalen-2-amine (800 mg, 2.97 mmol) in anh.DMF (4 mL) at RT are added potassium carbonate (616 mg, 4.46 mmol) andiodomethane (0.374 mL, 5.95 mmol) and the RM is stirred at RT for 5.5 h.Water and Et₂O are added and the layers are separated. The aqueous layeris extracted twice with Et₂O and the combined organic layers are washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=7/3)affords 3-iodo-N-methylnaphthalen-2-amine as a yellow oil. LC-MS B:t_(R)=1.04 min; [M+H]⁺=284.05.

A.1.12. 6-Chloro-N-(2-(1-chloronaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1-chloronaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.96 min; [M+H]⁺=317.99.

A.1.12.1. 2-(1-Chloronaphthalen-2-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1-chloronaphthalen-2-yl)ethyl)carbamate. LC-MS A: t_(R)=0.59 min;[M+H]⁺=206.13.

A.1.12.2. Tert-butyl (2-(1-chloronaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 2-bromo-1-chloronaphthalene. LC-MS A: t_(R)=0.98min; no ionization.

A.1.13.6-Chloro-N-(2-(3-((triisopropylsilyl)ethynyl)naphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(3-((triisopropylsilyl)ethynyl)naphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=1.20 min; [M+H]⁺=464.16.

A.1.13.1. 2-(3-((Triisopropylsilyl)ethynyl)naphthalen-2-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using the intermediate A.1.13.2. LC-MS A: t_(R)=0.90min: [M+H]⁺=352.17.

A.1.13.2. Preparation of the Intermediate A.1.13.2

To a solution of intermediate A.1.13.3. (412 mg, 0.79 mmol) in TEA (7mL) are added successively copper(I) iodide (21 mg, 0.11 mmol) andPdCl₂(PPh₃)₂ (28 mg, 0.039 mmol). The mixture is then degassed withnitrogen and (triisopropylsilyl)acetylene (0.356 mL, 1.59 mmol) isadded. The RM is heated to 50° C., under nitrogen, overnight. The RM isthen filtered over celite and the filtrate is concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=4/1) affordsintermediate A.1.13.2. as a brown oil (361 mg, 83%). LC-MS A: t_(R)=1.27min; no ionization.

A.1.13.3. Preparation of the Intermediate A.1.13.3

A solution of intermediate A.1.13.4. (390 mg, 1.01 mmol) and TEA (0.365mL, 2.62 mmol) in anh. DCM (10 mL) is treated portionwise at RT with1,1,1-trifluoro-N-phenyl-N-((trifuoromethyl)sulfonyl)methanesulfonamide(617 mg, 1.71 mmol) and the RM is stirred at RT, under nitrogen,overnight. The RM is then concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=9/1) affordsintermediate A.1.13.3. as a colorless solid (411 mg, 79%). LC-MS A:t_(R)=1.12 min; no ionization.

A.1.13.4. Preparation of the Intermediate A.1.13.4

A suspension of intermediate A.1.13.5. (528 mg, 1.08 mmol) in MeOH (11mL) is treated at RT with 2.8 M aq. NaOH (3.85 mL, 10.78 mmol) and theRM is heated to 55° C. for 20 min. The RM is then allowed to cool to RTand MeOH is removed under reduced pressure. Sat. aq. NH₄Cl is added, thelayers are separated and the aqueous layer is extracted three times withDCM. The combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure affordingintermediate A.1.13.4. as an off-white solid (390 mg, 93%). LC-MS A:t_(R)=0.99 min; no ionization.

A.1.13.5. Preparation of the Intermediate A.1.13.5

A solution of intermediate A.1.13.6. (456 mg, 1.18 mmol) in MeCN (12 mL)is treated at RT with di-tert-butyl dicarbonate (337 mg, 1.53 mmol) and4-(dimethylamino)pyridine (14 mg, 0.11 mmol), and the RM is heated to60° C. for 1.5 h. A second addition of di-tert-butyl dicarbonate (128mg, 0.58 mmol) is then performed and heating at 60° C. is continued for30 min. The RM is allowed to cool to RT, sat. aq. NH₄Cl is added, andthe layers are separated. The aqueous layer is extracted three timeswith EtOAc. The combined organic layers are dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords intermediate A.1.13.5. as acolorless oil (528 mg, 92%). LC-MS A: t_(R)=1.11 min; no ionization.

A.1.13.6. Tert-butyl(2-(3-((tert-butoxycarbonyl)oxy)naphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 3-bromonaphthalen-2-yl tert-butyl carbonate.LC-MS A: t_(R)=1.01 min: [M+H]⁺=388.30.

A.1.13.7. 3-Bromonaphthalen-2-yl tert-butyl carbonate

A solution of 3-bromonaphthalen-2-ol (410 mg, 1.82 mmol) in MeCN (18 mL)is treated at RT with di-tert-butyl dicarbonate (521 mg, 2.37 mmol) and4-(dimethylamino)pyridine (22 mg, 0.18 mmol). The RM is then heated to50° C. for 45 min. The RM is allowed to cool to RT, sat. aq. NH₄Cl isadded, and the layers are separated. The aqueous layer is extractedthree times with EtOAc. The combined organic layers are dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords 3-bromonaphthalen-2-yltert-butyl carbonate as a colorless solid (643 mg, quantitative). LC-MSA: t_(R)=1.00 min; no ionization.

A.1.14. 3-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)-2-naphthonitrile

The title compound is prepared according to the procedure describedabove in A.1.1. using 3-(2-aminoethyl)-2-naphthonitrile hydrochloride.LC-MS A: t_(R)=0.89 min; [M+H]⁺=309.06.

A.1.14.1. 3-(2-Aminoethyl)-2-naphthonitrile hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using intermediate A.1.14.2. (with R=H, Boc). LC-MS A:t_(R)=0.56 min; [M+H]⁺=197.22.

A.1.14.2. Preparation of Intermediate A.1.14.2

To a solution of intermediate A.1.14.3. (500 mg, 1.11 mmol) in anh. DMF(6 mL) are added successively zinc cyanide (160 mg, 1.33 mmol),Pd₂(dba)₃ (52 mg, 0.055 mmol), Xantphos (66 mg, 0.11 mmol) and TMEDA (33μL, 0.22 mmol). The RM is heated to 140° C. for 20 min. The RM isallowed to cool to RT and is then filtered over celite. Water and Et₂Oare added, the layers are separated and the aqueous layer is extractedtwice with Et₂O. The combined organic layers are dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=85/15) affords intermediate A.1.14.2.(R=Boc) as a pale yellow solid (211 mg, 48%). LC-MS A: t_(R)=1.05 min;no ionisation. Intermediate A.1.14.2. (R=H) is also isolated as acolorless solid (81 mg). LC-MS A: t_(R)=0.92 min; no ionization.

A.1.14.3. Preparation of the Intermediate A.1.14.3

A solution of tert-butyl (2-(3-bromonaphthalen-2-yl)ethyl)carbamate(1.52 g, 4.34 mmol) in MeCN (20 mL) is treated at RT with di-tert-butyldicarbonate (1.24 g, 5.64 mmol) and 4-(dimethylamino)pyridine (54 mg,0.43 mmol). The RM is then heated to 50° C. for 15 h. The RM is allowedto cool to RT, sat. aq. NH₄Cl is added, and the layers are separated.The aqueous layer is extracted three times with EtOAc. The combinedorganic layers are dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords intermediate A.1.14.3. as an orange oil (1.64g, 84%). LC-MS A: t_(R)=1.11 min; no ionization.

A.1.14.4. Tert-butyl (2-(3-bromonaphthalen-2-yl)ethyl)carbamate

A cooled (0° C.) solution of 2-(3-bromonaphthalen-2-yl)ethan-1-amine(1.85 g, 7.41 mmol) and DIPEA (2.54 mL, 14.80 mmol) in DCM (25 mL) istreated with a solution of di-tert-butyl dicarbonate (1.94 g, 8.89 mmol)in DCM (10 mL). The RM is further stirred at 0° C. for 15 min and thenat RT for 15 h. Water is added and the layers are separated. The organiclayer is then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/2) affords tert-butyl(2-(3-bromonaphthalen-2-yl)ethyl)carbamate as an orange solid (1.72 g,66%). LC-MS A: t_(R)=0.99 min; no ionization.

A.1.14.5. 2-(3-Bromonaphthalen-2-yl)ethan-1-amine

95% H₂SO₄ (0.47 mL) is added dropwise to a cooled (−10° C.) solution ofLAH (2 M in THF, 17.20 mL, 34.40 mmol) and the mixture is stirred at−10° C. for 20 min. A solution of 2-bromo-3-(2-nitrovinyl)naphthalene(2.14 g, 7.69 mmol) in anh. THE (25 mL) is then added dropwise andstirring is continued at −10° C. for 25 min and then at RT for 30 min.The RM is cooled to 0° C. and treated successively with 2-propanol (17mL) and with 2.8 M aq. NaOH (3.4 mL). The resulting suspension is thenfiltered and the filtrate is concentrated under reduced pressureaffording 2-(3-bromonaphthalen-2-yl)ethan-1-amine as a brown gel (1.73g, 90%). LC-MS A: t_(R)=0.61 min; [M+H]⁺=250.11.

A.1.14.6. 2-Bromo-3-(2-nitrovinyl)naphthalene

To a solution of 3-bromo-2-naphthaldehyde (1.95 g, 6.91 mmol) innitromethane (14 mL) are added successively 4A molecular sieves (266mg), butylamine (81 μL, 0.81 mmol) and acetic acid (80 μL, 1.41 mmol).The RM is heated to 90° C. for 20 min. The RM is then filtered and thefiltrate is concentrated under reduced pressure affording2-bromo-3-(2-nitrovinyl)naphthalene as a yellow solid (2.14 g,quantitative). LC-MS A: t_(R)=0.98 min: no ionization.

A.1.14.7. 3-Bromo-2-naphthaldehyde

To a cooled (−20° C.) solution of 2,3-dibromonaphthalene (3.12 g, 10.70mmol) in anh. THE (45 mL) is added dropwise a solution ofisopropylmagnesium chloride lithium chloride complex (1.3 M in THF,12.40 mL, 16.12 mmol) and the RM is further stirred at −20° C., undernitrogen, for 30 min. Anh. DMF (4.12 mL, 53.57 mmol) is then addeddropwise and stirring at −20° C. is continued for 30 min. The RM issuccessively treated with water (35 mL) and 12 M aq. HCl (4.7 mL) and isallowed to warm-up to RT. Et₂O is added, the layers are separated, andthe aq. layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=9/1) affords 3-bromo-2-naphthaldehyde as a pale yellowsolid (1.50 g, 60%). LC-MS A: t_(R)=0.90 min; no ionization.

A.1.15.6-Chloro-N-(2-(1-((triisopropylsilyl)ethynyl)naphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(1-((triisopropylsilyl)ethynyl)naphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=1.21 min; [M+H]⁺=464.16.

A.1.15.1. 2-(1-((Triisopropylsilyl)ethynyl)naphthalen-2-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1-((triisopropylsilyl)ethynyl)naphthalen-2-yl)ethyl)carbamate. LC-MSA: t_(R)=0.88 min; [M+H]⁺=352.16.

A.1.15.2. Tert-butyl(2-(1-((triisopropylsilyl)ethynyl)naphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.13.2. using tert-butyl(2-(1-iodonaphthalen-2-yl)ethyl)carbamate. LC-MS A: t_(R)=1.20 min;[M+H]⁺=452.23.

A.1.15.3. Tert-butyl (2-(1-iodonaphthalen-2-yl)ethyl)carbamate

To a mixture of tert-butyl (2-(1-bromonaphthalen-2-yl)ethyl)carbamate(500 mg, 1.43 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (22μL, 0.14 mmol) in dioxane (2 mL) at RT are added copper(I) iodide (14mg, 0.07 mmol) and sodium iodide (432 mg, 2.86 mmol). The RM is refluxed(110° C.) for 3 days. The RM is then allowed to cool to RT, water andDCM are added, and the layers are separated. The aqueous layer isextracted twice with DCM and the combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=4/1) affordstert-butyl (2-(1-iodonaphthalen-2-yl)ethyl)carbamate as a yellow solid(330 mg, 58%). LC-MS A: t_(R)=1.00 min; no ionization.

A.1.15.4. Tert-butyl (2-(1-bromonaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.14.4. using 2-(1-bromonaphthalen-2-yl)ethan-1-amine. LC-MSA: t_(R)=0.99 min; no ionization.

A.1.15.5. 2-(1-Bromonaphthalen-2-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.14.5. using 1-bromo-2-(2-nitrovinyl)naphthalene. LC-MS A:t_(R)=0.60 min: [M+H]⁺=250.14.

A.1.15.6. 1-Bromo-2-(2-nitrovinyl)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.14.6. using 1-bromo-2-naphthaldehyde. LC-MS A: t_(R)=0.98min; no ionization.

A.1.16. 2-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)-1-naphthonitrile

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(2-aminoethyl)-1-naphthonitrile hydrochloride.LC-MS A: t_(R)=0.89 min; [M+H]⁺=309.06.

A.1.16.1. 2-(2-Aminoethyl)-1-naphthonitrile hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1-cyanonaphthalen-2-yl)ethyl)carbamate. LC-MS A: t_(R)=0.56 min;[M+H]⁺=197.20.

A.1.16.2. Tert-butyl (2-(1-cyanonaphthalen-2-yl)ethyl)carbamate

The title compound is synthesized according to the procedure describedabove in A.1.14.2. using tert-butyl(2-(1-bromonaphthalen-2-yl)ethyl)carbamate (preparation described inA.1.15.4.). LC-MS A: t_(R)=0.92 min; no ionization.

A.1.17. N-(2-(1-Aminonaphthalen-2-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(2-aminoethyl)naphthalen-1-amine hydrochloride.LC-MS A: t_(R)=0.81 min; [M+H]⁺=299.08.

A.1.17.1. 2-(2-Aminoethyl)naphthalen-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1-aminonaphthalen-2-yl)ethyl)carbamate. LC-MS A: t_(R)=0.49 min;[M+H]⁺=187.29.

A.1.17.2. Tert-butyl (2-(1-aminonaphthalen-2-yl)ethyl)carbamate

The title compound is synthesized according to the procedure describedabove in A.1.1.2. using 2-bromonaphthalen-1-amine. LC-MS A: t_(R)=0.84min; [M+H]⁺=287.18.

A.1.18. 6-Chloro-N-(2-(1-vinylnaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1-vinylnaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.97 min; [M+H]⁺=310.09.

A.1.18.1. 2-(1-Vinylnaphthalen-2-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1-vinylnaphthalen-2-yl)ethyl)carbamate. LC-MS A: t_(R)=0.62 min;[M+H]⁺=198.22.

A.1.18.2. Tert-butyl (2-(1-vinylnaphthalen-2-yl)ethyl)carbamate

A suspension of tert-butyl (2-(1-bromonaphthalen-2-yl)ethyl)carbamate(800 mg, 2.28 mmol; preparation described in A.1.15.4.),2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane pyridine complex (289 mg,1.14 mmol) and 2 M aq. K₂CO (2.28 mL, 4.56 mmol) in dioxane (22 mL) isdegassed with nitrogen. Pd(PPhs)₄ (135 mg, 0.11 mmol) is added and themixture is degassed again with nitrogen. The RM is then heated to 90°C., under nitrogen, overnight. The RM is allowed to cool to RT, dilutedwith DCM and sat. aq. NaHCO₃ is added. The layers are separated and theaqueous layer is extracted twice with DCM. The combined organic layersare then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=4/1) affords tert-butyl(2-(1-vinylnaphthalen-2-yl)ethyl)carbamate as a yellow oil (582 mg,86%). LC-MS A: t_(R)=0.99 min; no ionization.

A.1.19.6-Chloro-N-(2-(3-methoxy-1-methylnaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(3-methoxy-1-methylnaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.09 min; [M+H]⁺=328.17.

A.1.19.1. 2-(3-Methoxy-1-methylnaphthalen-2-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-methoxy-1-methylnaphthalen-2-yl)ethyl)carbamate. LC-MS B:t_(R)=0.65 min; [M+H]⁺=216.30.

A.1.19.2. Tert-butyl(2-(3-methoxy-1-methylnaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 3-methoxy-1-methylnaphthalen-2-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.10 min; [M+H]⁺=316.26.

A.1.19.3. 3-Methoxy-1-methylnaphthalen-2-yl trifluoromethanesulfonate

A solution of 3-methoxy-1-methylnaphthalen-2-ol (802 mg, 4.26 mmol) andTEA (1.54 mL, 11.10 mmol) in anh. DCM (42 mL) is treated portionwise atRT with1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.587 g, 7.24 mmol) and the RM is stirred at RT, under nitrogen,overnight. The RM is then concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords3-methoxy-1-methylnaphthalen-2-yl trifluoromethanesulfonate as acolorless oil (1.09 g, 80%). LC-MS B: t_(R)=1.13 min; no ionization.

A.1.19.4. 3-Methoxy-1-methylnaphthalen-2-ol

A mixture of 3-methoxy-2-(methoxymethoxy)-1-methylnaphthalene (1.127 g,4.85 mmol) in MeOH (9 mL) and DCM (9 mL) is treated with 12 M aq. HCl(0.80 mL; 9.60 mmol) and the resulting suspension is stirred at RTovernight. Water and DCM are added and the layers are separated. Theaqueous layer is extracted twice with DCM and the combined organiclayers are washed with brine, dried over MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/7) affords 3-methoxy-1-methylnaphthalen-2-ol as acolorless solid (802 mg, 88%). LC-MS B: t_(R)=0.91 min; no ionization.

A.1.19.5. 3-Methoxy-2-(methoxymethoxy)-1-methylnaphthalene

A mixture of 1-bromo-3-methoxy-2-(methoxymethoxy)naphthalene (1.50 g,5.05 mmol) and Cs₂CO₃ (4.984 g, 15.10 mmol) in DMF (20 mL) is degassedwith nitrogen. Pd(PPhs)₄ (583 mg, 0.50 mmol) and2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (659 mg, 5.25 mmol) arethen added and the mixture is degassed again with nitrogen. The RM isthen heated to 90° C., under nitrogen, overnight. The RM is allowed tocool to RT, and diluted with Et₂O and water. The layers are separatedand the aqueous layer is extracted twice with Et₂O. The combined organiclayers are then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords3-methoxy-2-(methoxymethoxy)-1-methylnaphthalene as a colorless oil (950mg, 81%). LC-MS B: t_(R)=0.99 min; [M+H]⁺=233.31.

A.1.19.6. 1-Bromo-3-methoxy-2-(methoxymethoxy)naphthalene

A cooled (0° C.) solution of 1-bromo-3-methoxynaphthalen-2-ol (3.00 g,11.30 mmol) in anh. DMF (50 mL) is treated portionwise with sodiumhydride (60% dispersion in mineral oil, 540 mg, 13.50 mmol) and themixture is stirred at RT, under nitrogen, for 15 min. To the resultingcooled (0° C.) mixture is then added chloromethyl methyl ether (1.71 mL,22.50 mmol) and stirring at RT is continued for 1.5 h. Water and Et₂Oare added and the layers are separated. The organic layer issuccessively washed with water and brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords1-bromo-3-methoxy-2-(methoxymethoxy)naphthalene as a colorless oil (3.29g, 98%). LC-MS B: t_(R)=1.03 min; no ionization.

A.1.20.6-Chloro-N-(2-(1-fluoro-3-methoxynaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1-fluoro-3-methoxynaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.07 min; [M+H]⁺=332.16.

A.1.20.1. 2-(1-Fluoro-3-methoxynaphthalen-2-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1-fluoro-3-methoxynaphthalen-2-yl)ethyl)carbamate. LC-MS B:t_(R)=0.64 min; [M+H]⁺=220.28.

A.1.20.2. Tert-butyl(2-(1-fluoro-3-methoxynaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 1-fluoro-3-methoxynaphthalen-2-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.09 min; [M+H]⁺=320.18.

A.1.20.3. 1-Fluoro-3-methoxynaphthalen-2-yl trifluoromethanesulfonate

A solution of 1-fluoro-3-methoxynaphthalen-2-ol (740 mg, 3.85 mmol) andTEA (1.40 mL, 10.00 mmol) in anh. DCM (38 mL) is treated portionwise atRT with1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(1.667 g, 4.62 mmol) and the RM is stirred at RT, under nitrogen,overnight. The RM is then concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords1-fluoro-3-methoxynaphthalen-2-yl trifluoromethanesulfonate as acolorless oil (1.02 g, 82%). LC-MS B: t_(R)=1.13 min; no ionization.

A.1.20.4. 1-Fluoro-3-methoxynaphthalen-2-ol

The title compound is prepared according to the procedure describedabove in A.1.19.4. using1-fluoro-3-methoxy-2-(methoxymethoxy)naphthalene. LC-MS B: t_(R)=0.84min; no ionization.

A.1.20.5. 1-Fluoro-3-methoxy-2-(methoxymethoxy)naphthalene

To a cooled (−78° C.) solution of1-bromo-3-methoxy-2-(methoxymethoxy)naphthalene (1.78 g, 5.99 mmol) inanh. Et₂O (60 mL) is added dropwise a solution of BuLi (1.6 M inhexanes, 11.30 mL, 18.08 mmol) and the RM is allowed to warm-up to 0° C.and is then further stirred at 0° C., under nitrogen, for 1 h. Asolution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (5.842 g,18.00 mmol) in anh. THE (60 mL) is added dropwise to the previousmixture and stirring is then continued at RT for 1 h. The cooled (0° C.)RM is then treated dropwise with water and is allowed to warm-up to RT.EtOAc is added and the layers are separated. The aqueous layer isextracted twice with EtOAc and the combined organic layers are washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=1/1)affords 1-fluoro-3-methoxy-2-(methoxymethoxy)naphthalene as a yellowsolid (1.23 g, 87%). LC-MS B: t_(R)=0.96 min; [M+H]⁺=237.11.

A.1.20.6. 1-Bromo-3-methoxy-2-(methoxymethoxy)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.19.6. using 1-bromo-3-methoxynaphthalen-2-ol. LC-MS B:t_(R)=1.03 min; no ionization.

A.1.21.3-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)-4-methyl-2-naphthonitrile

The title compound is prepared according to the procedure describedabove in A.1.1. using 3-(2-aminoethyl)-4-methyl-2-naphthonitrilehydrochloride. LC-MS B: t_(R)=1.03 min; [M+H]⁺=323.12.

A.1.21.1. 3-(2-Aminoethyl)-4-methyl-2-naphthonitrile hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-cyano-1-methylnaphthalen-2-yl)ethyl)carbamate. LC-MS B: t_(R)=0.61min; [M+H]⁺=211.28.

A.1.21.2. Tert-butyl (2-(3-cyano-1-methylnaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 3-cyano-1-methylnaphthalen-2-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.06 min; [M+H]⁺=311.28.

A.1.21.3. 3-Cyano-1-methylnaphthalen-2-yl trifluoromethanesulfonate

The title compound is prepared according to the procedure describedabove in A.1.20.3. using 3-hydroxy-4-methyl-2-naphthonitrile. LC-MS B:t_(R)=1.10 min; no ionization.

A.1.21.4. 3-Hydroxy-4-methyl-2-naphthonitrile

To a solution of 3-bromo-1-methylnaphthalen-2-ol (2.28 g, 9.62 mmol) inanh. DMF (60 mL) are added successively zinc cyanide (1.383 g, 11.50mmol), Pd₂(dba)₃ (454 mg, 0.48 mmol), Xantphos (574 mg, 0.96 mmol) andTMEDA (291 μL, 1.92 mmol). The RM is heated to 140° C. for 20 min. TheRM is allowed to cool to RT and is then filtered over celite. Water andEt₂O are added, the layers are separated and the aqueous layer isextracted twice with Et₂O. The combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=1/1) affords3-hydroxy-4-methyl-2-naphthonitrile as a yellow solid (1.54 g, 87%).LC-MS B: t_(R)=0.87 min: no ionization.

A.1.21.5. 3-Bromo-2-(methoxymethoxy)-1-methylnaphthalene

To a cooled (0° C.) solution of 2-(methoxymethoxy)-1-methylnaphthalene(3.06 g, 15.10 mmol) in anh. Et₂O (168 mL) is added dropwise a solutionof BuLi (1.6 M in hexanes, 18.90 mL, 30.24 mmol) and the RM is allowedto warm-up to RT and is then further stirred at RT, under nitrogen, for2 h. Commercially available 1,2-dibromoethane (5.27 mL, 60.50 mmol) isadded dropwise to the previous mixture and stirring is then continued atRT for 1.5 h. The cooled (0° C.) RM is then treated dropwise with sat.aq. NH₄Cl and is allowed to warm-up to RT. EtOAc is added and the layersare separated. The aqueous layer is extracted twice with EtOAc and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords3-bromo-2-(methoxymethoxy)-1-methylnaphthalene as a yellow oil (3.36 g,79%). LC-MS B: t_(R)=1.05 min; [M+H]⁺=281.03.

A.1.21.6. 2-(Methoxymethoxy)-1-methylnaphthalene

The title compound is prepared according to the procedure describedabove in A.1.19.6. using 1-methylnaphthalen-2-ol. LC-MS B: t_(R)=0.99min; [M+H]⁺=203.18.

A.1.22.3-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)-4-fluoro-2-naphthonitrile

The title compound is prepared according to the procedure describedabove in A.1.1. using 3-(2-aminoethyl)-4-fluoro-2-naphthonitrilehydrochloride. LC-MS B: t_(R)=0.99 min; [M+H]⁺=327.09.

A.1.22.1. 3-(2-Aminoethyl)-4-fluoro-2-naphthonitrile hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-cyano-1-fluoronaphthalen-2-yl)ethyl)carbamate. LC-MS B: t_(R)=0.58min; [M+H]⁺=215.27.

A.1.22.2. Tert-butyl (2-(3-cyano-1-fluoronaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 3-cyano-1-fluoronaphthalen-2-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.04 min; [M+H]⁺=315.22.

A.1.22.3. 3-Cyano-1-fluoronaphthalen-2-yl trifluoromethanesulfonate

The title compound is prepared according to the procedure describedabove in A.1.19.3. using 4-fluoro-3-hydroxy-2-naphthonitrile. LC-MS B:t_(R)=1.09 min; no ionization.

A.1.22.4. 4-Fluoro-3-hydroxy-2-naphthonitrile

To a solution of 4-fluoro-3-(methoxymethoxy)-2-naphthaldehyde (1.15 g,4.91 mmol) in anh. pyridine (1.66 mL, 20.50 mmol) is added hydroxylaminehydrochloride (383 mg, 5.45 mmol) and the mixture is stirred at RT for 1h. The RM is heated to 80° C., and acetic anhydride (0.89 mL, 9.42 mmol)is then added dropwise. After completion of the addition, the mixture isheated to 100° C. for 20 min. The RM is then allowed to cool to RT,diluted with EtOAc and washed successively with 1 M aq. HCl and sat. aq.NaHCO₃. The organic layer is dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toEtOAc) affords 4-fluoro-3-hydroxy-2-naphthonitrile as a pale yellowsolid (630 mg, 69%). LC-MS B: t_(R)=0.84 min: no ionization.

A.1.22.5. 4-Fluoro-3-(methoxymethoxy)-2-naphthaldehyde

To a cooled (−78° C.) solution of 1-fluoro-2-(methoxymethoxy)naphthalene(2.533 g, 12.30 mmol) in anh. THE (100 mL) is added dropwise a solutionof BuLi (1.6 M in hexanes, 19.20 mL, 30.72 mmol) and the RM is furtherstirred at −78° C., under nitrogen, for 1 h. Anh. DMF (1.90 mL, 24.60mmol) is then added dropwise to the previous mixture, and stirring at−78° C. is continued for 15 min. The cooled RM is then treated dropwisewith sat. aq. NH₄Cl and is allowed to warm-up to RT. EtOAc is added, thelayers are separated, and the aqueous layer is extracted twice withEtOAc. The combined organic layers are washed with brine, dried overanh. MgSO₄, filtered and concentrated under reduced pressure affording4-fluoro-3-(methoxymethoxy)-2-naphthaldehyde as a yellow oil (2.90 g,quantitative). LC-MS B: t_(R)=0.95 min; [M+H]⁺=235.27.

A.1.22.6. 1-Fluoro-2-(methoxymethoxy)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.19.6. using 1-fluoronaphthalen-2-ol. LC-MS B: t_(R)=0.97min; [M+H]⁺=207.25.

A.1.23.6-Chloro-N-(2-(1,3-difluoronaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1,3-difluoronaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.06 min; [M+H]⁺=320.13.

A.1.23.1. 2-(1,3-Difluoronaphthalen-2-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1,3-difluoronaphthalen-2-yl)ethyl)carbamate. LC-MS B: t_(R)=0.60min; [M+H]⁺=208.26.

A.1.23.2. Tert-butyl (2-(1,3-difluoronaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 1,3-difluoronaphthalen-2-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.08 min; no ionization.

A.1.23.3. 1,3-Difluoronaphthalen-2-yl trifluoromethanesulfonate

The title compound is prepared according to the procedure describedabove in A.1.20.3. using 1,3-difluoronaphthalen-2-ol. LC-MS B:t_(R)=1.12 min; no ionization.

A.1.23.4. 1,3-Difluoronaphthalen-2-ol

The title compound is prepared according to the procedure describedabove in A.1.19.4. using 1,3-difluoro-2-(methoxymethoxy)naphthalene.LC-MS B: t_(R)=0.85 min; no ionization.

A.1.23.5. 1,3-Difluoro-2-(methoxymethoxy)naphthalene

To a cooled (−78° C.) solution of 1-fluoro-2-(methoxymethoxy)naphthalene(1.50 g, 7.27 mmol; preparation described in A.1.22.6.) in anh. THE (35mL) is added dropwise a solution of BuLi (1.6 M in hexanes, 9.06 mL,14.49 mmol) and the mixture is further stirred at −78° C., undernitrogen, for 1 h. A solution ofN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (5.202 g, 16.00 mmol) inanh. THE (10 mL) is added dropwise to the previous mixture and stirringis then continued at 0° C. for 15 min. The RM is treated dropwise withsat. aq. NH₄Cl and is then allowed to warm-up to RT. EtOAc is added andthe layers are separated. The aqueous layer is extracted twice withEtOAc and the combined organic layers are washed with brine, dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords1,3-difluoro-2-(methoxymethoxy)naphthalene as a yellow oil (1.30 g,80%). LC-MS B: t_(R)=1.00 min; no ionization.

A.1.24.6-Chloro-N-(2-(4-chloro-3-methoxynaphthalen-2-yl)ethyl)pyrimidin-4-amine

A solution of1-chloro-3-(2-((6-chloropyrimidin-4-yl)amino)ethyl)naphthalen-2-ol (100mg, 0.29 mmol) in anh. DMF (3 mL) is treated at RT with cesium carbonate(117 mg, 0.35 mmol) and iodomethane (38 μL, 0.61 mmol) and the RM isstirred at RT, under nitrogen, for 3 h. Water is added and the mixtureis extracted three times with Et₂O. The combined organic layers are thenwashed twice with water, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure affording6-chloro-N-(2-(4-chloro-3-methoxynaphthalen-2-yl)ethyl)pyrimidin-4-amineas an off-white solid (98 mg, 94%). LC-MS B: t_(R)=1.08 min;[M+H]⁺=348.13.

A.1.24.1.1-Chloro-3-(2-((6-chloropyrimidin-4-yl)amino)ethyl)naphthalen-2-ol

A mixture of6-chloro-N-(2-(4-chloro-3-(methoxymethoxy)naphthalen-2-yl)ethyl)pyrimidin-4-amine(390 mg, 1.03 mmol) in MeOH (2 mL) and DCM (2 mL) is treated with 12 Maq. HCl (0.17 mL; 2.04 mmol) and the resulting suspension is stirred atRT overnight. Water and DCM are then added, and the resultingprecipitate is filtered. The isolated solid is further dried under highvacuum affording1-chloro-3-(2-((6-chloropyrimidin-4-yl)amino)ethyl)naphthalen-2-ol as acolorless solid (304 mg, 88%). LC-MS B: t_(R)=0.99 min; [M+H]⁺=334.12.

A.1.24.2.6-Chloro-N-(2-(4-chloro-3-(methoxymethoxy)naphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(4-chloro-3-(methoxymethoxy)naphthalen-2-yl)ethan-1-amine. LC-MS B:t_(R)=1.08 min; [M+H]⁺=378.17.

A.1.24.3. 2-(4-Chloro-3-(methoxymethoxy)naphthalen-2-yl)ethan-1-amine

95% H₂SO₄ (88 μL) is added dropwise to a cooled (−10° C.) solution ofLAH (2 M in THF, 2.51 mL, 5.02 mmol) and the mixture is stirred at −10°C. for 20 min. A solution of1-chloro-2-(methoxymethoxy)-3-(2-nitrovinyl)naphthalene (420 mg, 1.43mmol) in anh. THE (10 mL) is then added dropwise and stirring iscontinued at −10° C. for 30 min, and then at 0° C. for 1 h. The RM istreated successively with 2-propanol (23 mL) and with 2.8 M aq. NaOH(0.6 mL), and is then allowed to warm-up to RT. The resulting suspensionis filtered and the filtrate is concentrated under reduced pressureaffording 2-(4-chloro-3-(methoxymethoxy)naphthalen-2-yl)ethan-1-amine asan orange oil (384 mg, quantitative). LC-MS B: t_(R)=0.68 min;[M+H]⁺=266.25.

A.1.24.4. 1-Chloro-2-(methoxymethoxy)-3-(2-nitrovinyl)naphthalene

To a solution of 4-chloro-3-(methoxymethoxy)-2-naphthaldehyde (910 mg,3.63 mmol) in nitromethane (7 mL) are added successively molecularsieves (4A, 95 mg), butylamine (42 μL, 0.42 mmol) and acetic acid (42μL, 0.74 mmol). The RM is heated to 90° C. for 25 min. The RM is thenfiltered and the filtrate is concentrated under reduced pressure.Purification by FC (from heptane to EtOAc) affords1-chloro-2-(methoxymethoxy)-3-(2-nitrovinyl)naphthalene as an orangesolid (420 mg, 39%). LC-MS B: t_(R)=1.08 min; no ionization.

A.1.24.5. 4-Chloro-3-(methoxymethoxy)-2-naphthaldehyde

To a cooled (−78° C.) solution of 1-chloro-2-(methoxymethoxy)naphthalene(810 mg, 3.64 mmol) in anh. THE (30 mL) is added dropwise a solution ofBuLi (1.6 M in hexanes, 5.70 mL, 9.12 mmol) and the RM is furtherstirred at −78° C., under nitrogen, for 1 h. Anh. DMF (0.563 mL, 7.28mmol) is then added dropwise to the previous mixture, and stirring at−78° C. is continued for 15 min. The cooled RM is then treated dropwisewith sat. aq. NH₄Cl and is allowed to warm-up to RT. EtOAc is added, thelayers are separated, and the aqueous layer is extracted twice withEtOAc. The combined organic layers are washed with brine, dried overanh. MgSO₄, filtered and concentrated under reduced pressure affording4-chloro-3-(methoxymethoxy)-2-naphthaldehyde as a pale yellow solid (910mg, 99%). LC-MS B: t_(R)=0.99 min; [M+H]⁺=251.24.

A.1.24.6. 1-Chloro-2-(methoxymethoxy)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.19.6. using 1-chloronaphthalen-2-ol. LC-MS B: t_(R)=1.01min; [M+H]⁺=223.18.

A.1.25.6-Chloro-N-(2-(4-fluoro-3-methoxynaphthalen-2-yl)ethyl)pyrimidin-4-amine

A solution of3-(2-((6-chloropyrimidin-4-yl)amino)ethyl)-1-fluoronaphthalen-2-ol (149mg, 0.46 mmol) in anh. DMF (6 mL) is treated at RT with cesium carbonate(183 mg, 0.56 mmol) and iodomethane (59 μL, 0.93 mmol) and the RM isstirred at RT, under nitrogen, for 1.5 h. Water is added and the mixtureis extracted three times with Et₂O. The combined organic layers are thenwashed twice with water, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords6-chloro-N-(2-(4-fluoro-3-methoxynaphthalen-2-yl)ethyl)pyrimidin-4-amineas a colorless solid (89 mg, 57%). LC-MS B: t_(R)=1.06 min;[M+H]⁺=332.20.

A.1.25.1.3-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)-1-fluoronaphthalen-2-ol

The title compound is prepared according to the procedure describedabove in A.1.19.4. using6-chloro-N-(2-(4-fluoro-3-(methoxymethoxy)naphthalen-2-yl)ethyl)pyrimidin-4-amine.LC-MS B: t_(R)=0.95 min; [M+H]⁺=318.16.

A.1.25.2.6-Chloro-N-(2-(4-fluoro-3-(methoxymethoxy)naphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(4-fluoro-3-(methoxymethoxy)naphthalen-2-yl)ethan-1-amine. LC-MS B:t_(R)=1.05 min; [M+H]⁺=362.20.

A.1.25.3. 2-(4-Fluoro-3-(methoxymethoxy)naphthalen-2-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.24.3. using1-fluoro-2-(methoxymethoxy)-3-(2-nitrovinyl)naphthalene. LC-MS B:t_(R)=0.65 min: [M+H]⁺=250.31.

A.1.25.4. 1-Fluoro-2-(methoxymethoxy)-3-(2-nitrovinyl)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.24.4. using 4-fluoro-3-(methoxymethoxy)-2-naphthaldehyde(preparation described in A.1.22.5.). LC-MS B: t_(R)=1.06 min;[M+H]⁺=278.40.

A.1.26. N-(2-(Benzo[b]thiophen-5-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzo[b]thiophen-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.01 min; [M+H]⁺=289.95.

A.1.26.1. 2-(Benzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(benzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.56 min;[M+H]⁺=178.12.

A.1.26.2. Tert-butyl (2-(benzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is synthesized according to the procedure describedabove in A.1.1.2. using 5-bromobenzo[b]thiophene. LC-MS B: t_(R)=1.03min; [M+H]⁺=278.03.

A.1.27. N-(2-(Benzo[b]thiophen-6-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzo[b]thiophen-6-yl)ethan-1-amine. LC-MS A:t_(R)=0.90 min; [M+H]⁺=290.05.

A.1.27.1. 2-(Benzo[b]thiophen-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using benzo[b]thiophene-6-carbaldehyde. LC-MS A:t_(R)=0.52 min; [M+H]⁺=178.27.

A.1.28.N-(2-(Benzo[b]thiophen-5-yl)ethyl)-6-chloro-2-methylpyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzo[b]thiophen-5-yl)ethan-1-aminehydrochloride (preparation described in A.1.26.1.) and4,6-dichloro-2-methylpyrimidine. LC-MS B: t_(R)=0.94 min; [M+H]⁺=303.99.

A.1.29.6-Chloro-N-(2-(3-methylbenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(3-methylbenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.03 min; [M+H]⁺=304.04.

A.1.29.1. 2-(3-Methylbenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-methylbenzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.58min; [M+H]⁺=192.18.

A.1.29.2. Tert-butyl (2-(3-methylbenzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is synthesized according to the procedure describedabove in A.1.1.2. using 5-bromo-3-methylbenzo[b]thiophene. LC-MS B:t_(R)=1.06 min: no ionization.

A.1.30.5-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)benzo[b]thiophene-3-carbonitrile

The title compound is prepared according to the procedure describedabove in A.1.1. using 5-(2-aminoethyl)benzo[b]thiophene-3-carbonitrilehydrochloride. LC-MS B: t_(R)=0.96 min; [M+H]⁺=315.01.

A.1.30.1. 5-(2-Aminoethyl)benzo[b]thiophene-3-carbonitrile hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-cyanobenzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.55min; [M+H]⁺=203.04.

A.1.30.2. Tert-butyl (2-(3-cyanobenzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is synthesized according to the procedure describedabove in A.1.1.2. using 5-bromobenzo[b]thiophene-3-carbonitrile. LC-MSB: t_(R)=0.99 min; [M+H]⁺=303.08.

A.1.30.3. 5-Bromobenzo[b]thiophene-3-carbonitrile

A well-stirred suspension of 5-bromobenzo[b]thiophene-3-carbaldehyde(1.00 g, 4.02 mmol) and sodium azide (392 mg, 6.03 mmol) in anh. MeCN (4mL) is treated at RT with a solution of trifluoromethanesulfonic acid(1.09 mL, 12.10 mmol) in anh. MeCN (10 mL). The RM is further stirred atRT, under nitrogen, for 0.5 h. Water is then added and the mixture isfiltered. The collected solid is washed with water and is then dissolvedin EtOAc. The organic layer is dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords 5-bromobenzo[b]thiophene-3-carbonitrile as ared solid (694 mg, 72%). LC-MS B: t_(R)=0.97 min; no ionization.

A.1.31.6-Chloro-N-(2-(6-methoxybenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(6-methoxybenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.04 min; [M+H]⁺=320.09.

A.1.31.1. 2-(6-Methoxybenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-methoxybenzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.58min; [M+H]⁺=208.19.

A.1.31.2. Tert-butyl (2-(6-methoxybenzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is synthesized according to the procedure describedabove in A.1.1.2. using 5-bromo-6-methoxybenzo[b]thiophene. LC-MS B:t_(R)=1.04 min; [M+H]⁺=308.12.

A.1.31.3. 5-Bromo-6-methoxybenzo[b]thiophene

A mixture of 5-bromo-6-methoxybenzo[b]thiophene-2-carboxylic acid (2.260g, 7.87 mmol) and copper(I) oxide (4.393 g, 30.70 mmol) in DMF (42 mL)is heated to 140° C. for 21 h. The RM is allowed to cool to RT and isfiltered over celite to remove copper salts that are washed with Et₂O.Water and Et₂O are added to the filtrate and the layers are separated.The aqueous layer is extracted twice with Et₂O and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords 5-bromo-6-methoxybenzo[b]thiophene as a paleorange solid (1.580 g, 87%). LC-MS B: t_(R)=0.99 min: no ionization.

A.1.31.4. 5-Bromo-6-methoxybenzo[b]thiophene-2-carboxylic acid

A mixture of methyl 5-bromo-6-methoxybenzo[b]thiophene-2-carboxylate(2.970 g, 9.86 mmol) in THE (80 mL), MeOH (9 mL) and water (27 mL) istreated portionwise with lithium hydroxide (709 mg, 29.60 mmol). The RMis stirred at RT overnight. The RM is then acidified by addition of 2 Maq. HCl and the organic solvents are removed under reduced pressure. Theresulting suspension is filtered and the separated solid is then washedwith water and dried under high vacuum to give5-bromo-6-methoxybenzo[b]thiophene-2-carboxylic acid as a colorlesssolid (2.260 g, 80%). LC-MS B: t_(R)=0.87 min; no ionization.

A.1.31.5. Methyl 5-bromo-6-methoxybenzo[b]thiophene-2-carboxylate

To a cooled (0° C.) mixture of 5-bromo-2-fluoro-4-methoxybenzaldehyde(2.500 g, 10.50 mmol) and potassium carbonate (2.224 g, 15.80 mmol) inDMF (15 mL) is added dropwise methyl 2-mercaptoacetate (0.99 mL, 10.50mmol). The RM is stirred at RT for 1 h, and then heated to 60° C.overnight. The RM is allowed to cool to RT and water is added. Theresulting suspension is filtered and the separated solid is then washedwith water and dried under high vacuum to give methyl5-bromo-6-methoxybenzo[b]thiophene-2-carboxylate as a yellow solid(2.970 g, 94%). LC-MS B: t_(R)=1.06 min; no ionization.

A.1.32.6-Chloro-N-(2-(6-ethoxybenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(6-ethoxybenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.07 min; [M+H]⁺=334.07.

A.1.32.1. 2-(6-Ethoxybenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-ethoxybenzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.65min; [M+H]⁺=222.10.

A.1.32.2. Tert-butyl (2-(6-ethoxybenzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is synthesized according to the procedure describedabove in A.1.1.2. using 5-bromo-6-ethoxybenzo[b]thiophene. LC-MS B:t_(R)=1.08 min; [M+H]⁺=322.02.

A.1.32.3. 5-Bromo-6-ethoxybenzo[b]thiophene

To a solution of 5-bromobenzo[b]thiophen-6-ol (190 mg, 0.82 mmol) inanh. DMF (8 mL) at RT are added cesium carbonate (270 mg, 0.82 mmol) andiodoethane (73 μL, 0.91 mmol) and the RM is stirred at RT, undernitrogen, for 1 h. Water and Et₂O are added and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure affording5-bromo-6-ethoxybenzo[b]thiophene as a yellow oil (241 mg,quantitative). LC-MS B: t_(R)=1.05 min; no ionization.

A.1.32.4. 5-Bromobenzo[b]thiophen-6-ol

To a cooled (−78° C.) solution of 5-bromo-6-methoxybenzo[b]thiophene(710 mg, 2.92 mmol; preparation described in A.1.31.3.) in anh. DCM (10mL) is added dropwise a solution of boron tribromide (1 M in DCM, 5.84mL, 5.84 mmol) and the RM is stirred at RT, under nitrogen, overnight.The RM is then poured onto ice-water and the layers are separated. Theaqueous layer is extracted twice with DCM and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords 5-bromobenzo[b]thiophen-6-ol as a pale orangesolid (190 mg, 28%). LC-MS B: t_(R)=0.86 min; no ionization.

A.1.33.5-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)benzo[b]thiophene-6-carbonitrile

The title compound is prepared according to the procedure describedabove in A.1.1. using 5-(2-aminoethyl)benzo[b]thiophene-6-carbonitrilehydrochloride. LC-MS B: t_(R)=0.94 min; [M+H]⁺=315.03.

A.1.33.1. 5-(2-Aminoethyl)benzo[b]thiophene-6-carbonitrile hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-cyanobenzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.54min; [M+H]⁺=203.15.

A.1.33.2. Tert-butyl (2-(6-cyanobenzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.14.2. using intermediate A.1.33.3. LC-MS B: t_(R)=1.00 min;[M+H]⁺=303.07.

A.1.33.3. Preparation of Intermediate A.1.33.3

The title compound is prepared according to the procedure describedabove in A.1.13.3. using intermediate

A.1.33.4. LC-MS B: t_(R)=1.26 min: no ionization A.1.33.4. Preparationof Intermediate A.1.33.4

The title compound is prepared according to the procedure describedabove in A.1.13.4. using intermediate

A.1.33.5. LC-MS B: t_(R)=1.10 min; [M+H]⁺=394.16 A.1.33.5. Preparationof Intermediate A.1.33.5

The title compound is prepared according to the procedure describedabove in A.1.13.5. using tert-butyl(2-(6-((tert-butoxycarbonyl)oxy)benzo[b]thiophen-5-yl)ethyl)carbamate.LC-MS B: t_(R)=1.24 min; no ionization.

A.1.33.6. Tert-butyl(2-(6-((tert-butoxycarbonyl)oxy)benzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromobenzo[b]thiophen-6-yl tert-butylcarbonate. LC-MS B: t_(R)=1.12 min; [M+H]⁺=394.17.

A.1.33.7. 5-Bromobenzo[b]thiophen-6-yl tert-butyl carbonate

The title compound is prepared according to the procedure describedabove in A.1.13.7. using 5-bromobenzo[b]thiophen-6-ol. LC-MS B:t_(R)=1.09 min; no ionization.

A.1.33.8. 5-Bromobenzo[b]thiophen-6-ol

A mixture of 5-bromo-6-(methoxymethoxy)benzo[b]thiophene (1.55 g, 5.67mmol) in MeOH (11 mL) and DCM (11 mL) is treated with 12 M aq. HCl (0.94mL; 11.28 mmol) and the resulting suspension is stirred at RT overnight.The RM is then concentrated under reduced pressure and the residue isfurther dried under high vacuum affording 5-bromobenzo[b]thiophen-6-olas a yellow solid. LC-MS B: t_(R)=0.85 min; no ionization.

A.1.33.9. 5-Bromo-6-(methoxymethoxy)benzo[b]thiophene

A mixture of 5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carboxylicacid (2.30 g, 7.25 mmol) and copper(I) oxide (259 mg, 1.81 mmol) in DMF(36 mL) is heated to 140° C. for 15 h. The RM is allowed to cool to RTand is filtered over celite to remove copper salts that are washed withEt₂O. Water and Et₂O are added to the filtrate and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=4/1) affords5-bromo-6-(methoxymethoxy)benzo[b]thiophene as a yellow oil (1.550 g,78%). LC-MS B: t_(R)=1.02 min; no ionization.

A.1.33.10. 5-Bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carboxylic acid

A mixture of methyl5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carboxylate (2.380 g, 7.19mmol) in THE (85 mL), MeOH (17 mL) and water (17 mL) is treatedportionwise with lithium hydroxide (516 mg, 21.60 mmol). The RM isstirred at RT for 3 h. The organic solvents are then removed underreduced pressure and the aqueous layer is acidified by addition of 1 Maq. HCl. The resulting suspension is filtered and the separated solid isthen washed with water and dried under high vacuum to give5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carboxylic acid as acolorless solid (2.30 g, quantitative). LC-MS B: t_(R)=0.88 min: noionization.

A.1.33.11. Methyl5-bromo-6-(methoxymethoxy)benzo[b]thiophene-2-carboxylate

The title compound is prepared according to the procedure describedabove in A.1.31.5. using 5-bromo-2-fluoro-4-(methoxymethoxy)benzaldehydeand methyl 2-mercaptoacetate. LC-MS B: t_(R)=1.04 min; no ionization.

A.1.33.12. 5-Bromo-2-fluoro-4-(methoxymethoxy)benzaldehyde

A cooled (0° C.) solution of 5-bromo-2-fluoro-4-hydroxybenzaldehyde(1.90 g, 8.68 mmol) in anh. DMF (40 mL) is treated portionwise withsodium hydride (60% dispersion in mineral oil, 347 mg, 8.68 mmol) andthe mixture is stirred at RT, under nitrogen, for 15 min. To theresulting cooled (0° C.) mixture is then added chloromethyl methyl ether(1.32 mL, 17.40 mmol) and stirring at RT is continued overnight. Waterand Et₂O are added and the layers are separated. The organic layer issuccessively washed with water and brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure to give5-bromo-2-fluoro-4-(methoxymethoxy)benzaldehyde as a pale yellow solid(2.33 g, quantitative). LC-MS B: t_(R)=0.90 min; no ionization.

A.1.33.13. 5-Bromo-2-fluoro-4-hydroxybenzaldehyde

A mixture of 5-bromo-2-fluoro-4-methoxybenzaldehyde (3.311 g, 13.90mmol) and lithium chloride (2.385 g, 55.70 mmol) in anh. DMF (60 mL) isheated to 140° C. overnight. The RM is allowed to cool to RT, pouredonto ice-water and is then acidified by addition of 12 M aq. HCl. Theresulting solution is extracted three times with EtOAc and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to heptane/EtOAc=7/3) affords5-bromo-2-fluoro-4-hydroxybenzaldehyde as a pale yellow solid (1.90 g,62%). LC-MS B: t_(R)=0.76 min; no ionization.

A.1.34. N-(2-(Benzofuran-6-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzofuran-6-yl)ethan-1-amine hydrochloride.LC-MS A: t_(R)=0.87 min; [M+H]⁺=273.99.

A.1.34.1. 2-(Benzofuran-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl (2-(benzofuran-6-yl)ethyl)carbamate.LC-MS A: t_(R)=0.48 min; [M+H]⁺=162.14.

A.1.34.2. Tert-butyl (2-(benzofuran-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 6-bromobenzofuran. LC-MS A: t_(R)=0.89 min; noionization.

A.1.35. N-(2-(Benzofuran-5-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzofuran-5-yl)ethan-1-amine. LC-MS A:t_(R)=0.86 min: [M+H]⁺=273.96.

A.1.35.1. 2-(Benzofuran-5-yl)ethan-1-amine

To a solution of benzofuran-5-carbaldehyde (600 mg, 4.02 mmol) innitromethane (4 mL) are added successively 4A molecular sieves (47 mg),butylamine (47 μL, 0.47 mmol) and acetic acid (47 μL, 0.82 mmol). The RMis heated to 90° C., under nitrogen, for 1 h. The RM is then filteredand the filtrate is concentrated under reduced pressure. Purification byFC (from heptane/DCM=4/1 to heptane/DCM=2/3) affords5-(2-nitrovinyl)benzofuran as a pale yellow solid (451 mg, 59%). LC-MSA: t_(R)=0.86 min; no ionisation

To a cooled (0° C.) solution of 5-(2-nitrovinyl)benzofuran (451 mg, 2.39mmol) in anh. THE (19 mL) is added dropwise a solution of lithiumaluminum hydride (2 M in THF, 4.17 mL, 8.34 mmol). The mixture is thenstirred at RT, under nitrogen, overnight. The cooled (0° C.) RM istreated successively with water (0.3 mL), 15% aq. NaOH (0.3 mL), andwater (1 mL). The resulting heterogeneous mixture is then filtered andthe separated solid is washed with Et₂O. The layers of the filtrate areseparated and the aqueous layer is extracted with Et₂O. The combinedorganic layers are then dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from DCM to DCM/MeOH/25% aq.NH₄OH=10/1/0.2) affords 2-(benzofuran-5-yl)ethan-1-amine as a paleyellow oil (182 mg, 47%). LC-MS A: t_(R)=0.49 min; [M+H]⁺=162.09.

A.1.36. 6-Chloro-N-(2-(6-methoxybenzofuran-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(6-methoxybenzofuran-5-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.89 min; [M+H]⁺=304.07.

A.1.36.1. 2-(6-Methoxybenzofuran-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-methoxybenzofuran-5-yl)ethyl)carbamate. LC-MS A: t_(R)=0.54 min;[M+H]⁺=192.24.

A.1.36.2. Tert-butyl (2-(6-methoxybenzofuran-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-6-methoxybenzofuran. LC-MS A: t_(R)=0.91min; [M+H]⁺=292.16.

A.1.36.3. 5-Bromo-6-methoxybenzofuran

To a solution of 5-bromo-2-hydroxy-4-methoxybenzaldehyde (5.00 g, 20.60mmol) in anh. DMF (40 mL) at RT are added successively ethyl2-bromoacetate (2.44 mL, 21.56 mmol), potassium carbonate (2.98 g, 21.56mmol) and potassium iodide (171 mg, 1.03 mmol). The RM is heated to 80°C., under nitrogen, for 80 min. The RM is then allowed to cool to RT.Water is added and the resulting precipitate is filtered and washed withwater. The obtained solid is then dissolved in EtOAc and this solutionis dried over anh. MgSO₄, filtered and concentrated under reducedpressure giving ethyl 2-(4-bromo-2-formyl-5-methoxyphenoxy)acetate as acolorless solid (6.68 g, quantitative). LC-MS A: t_(R)=0.86 min;[M+H]⁺=316.95.

To a solution of ethyl 2-(4-bromo-2-formyl-5-methoxyphenoxy)acetate(6.68 g, 20.60 mmol) in EtOH (27 mL) at RT is added 1 M aq. NaOH (27.40mL, 27.40 mmol) and the RM is heated to 50° C., under nitrogen, for 20min. The RM is then allowed to cool to RT and is treated with 1 M aq.HCl (27.40 mL). EtOH is removed under reduced pressure and the residualaqueous mixture is extracted twice with DCM. The combined organic layersare washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure affording2-(4-bromo-2-formyl-5-methoxyphenoxy)acetic acid as a pale yellow solid(6.01 g, 100%). LC-MS A: t_(R)=0.71 min; [M+H]⁺=288.99.

A mixture of 2-(4-bromo-2-formyl-5-methoxyphenoxy)acetic acid (1.50 g,5.19 mmol) in acetic anhydride (6.13 mL, 64.84 mmol) at RT is treatedwith sodium acetate (1.27 g, 15.48 mmol) and is then heated at reflux(150° C.), under nitrogen, for 15 h. The RM is allowed to cool to RT,diluted with toluene (20 mL) and treated with 1 M aq. NaOH (40 mL).After stirring at RT for 1 h, the RM is diluted with water and extractedtwice with EtOAc. The combined organic layers are washed with brine,dried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=9/1) affords5-bromo-6-methoxybenzofuran as a colorless oil (0.74 g, 63%). LC-MS A:t_(R)=0.87 min; no ionization.

A.1.37. 6-Chloro-N-(2-(6-fluorobenzofuran-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(6-fluorobenzofuran-5-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.88 min; [M+H]⁺=292.07.

A.1.37.1. 2-(6-Fluorobenzofuran-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-fluorobenzofuran-5-yl)ethyl)carbamate. LC-MS A: t_(R)=0.51 min;[M+H]⁺=180.27.

A.1.37.2. Tert-butyl (2-(6-fluorobenzofuran-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-6-fluorobenzofuran. LC-MS A: t_(R)=0.91min; no ionization.

A.1.37.3. 5-Bromo-6-fluorobenzofuran

The title compound is prepared according to the procedure describedabove in A.1.36.3. using 5-bromo-4-fluoro-2-hydroxybenzaldehyde. LC-MSA: t_(R)=0.88 min; no ionization.

A.1.38. 6-Chloro-N-(2-(5-methoxybenzofuran-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(5-methoxybenzofuran-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.89 min; [M+H]⁺=304.06.

A.1.38.1. 2-(5-Methoxybenzofuran-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(5-methoxybenzofuran-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.53 min:[M+H]⁺=192.22.

A.1.38.2. Tert-butyl (2-(5-methoxybenzofuran-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 6-bromo-5-methoxybenzofuran. LC-MS A: t_(R)=0.91min; no ionization.

A.1.38.3. 6-Bromo-5-methoxybenzofuran and6-bromo-5-methoxybenzofuran-2-carboxylic acid

To a solution of 4-bromo-2-hydroxy-5-methoxybenzaldehyde (3.00 g, 12.60mmol) in anh. DMF (25 mL) at RT are added successively ethyl2-bromoacetate (1.50 mL, 13.20 mmol), potassium carbonate (1.828 g,13.20 mmol) and potassium iodide (105 mg, 0.63 mmol). The RM is heatedto 80° C., under nitrogen, for 30 min. The RM is then allowed to cool toRT. Water is added and the resulting precipitate is filtered and washedwith water. The obtained solid is then dissolved in EtOAc and thissolution is dried over anh. MgSO₄, filtered and concentrated underreduced pressure giving ethyl2-(5-bromo-2-formyl-4-methoxyphenoxy)acetate as a colorless solid (4.027g, 100%). LC-MS A: t_(R)=0.87 min; [M+H]⁺=316.95

To a solution of ethyl 2-(5-bromo-2-formyl-4-methoxyphenoxy)acetate(4.027 g, 12.60 mmol) in EtOH (16 mL) at RT is added 1 M aq. NaOH (16.5mL, 16.5 mmol) and the RM is heated to 50° C., under nitrogen, for 30min. The RM is then allowed to cool to RT and is treated with 1 M aq.HCl (16.5 mL). EtOH is removed under reduced pressure and the residualaqueous mixture is extracted twice with DCM. The combined organic layersare washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure affording2-(5-bromo-2-formyl-4-methoxyphenoxy)acetic acid as a yellow solid(3.447 g, 94%). LC-MS A: t_(R)=0.70 min; [M+H]⁺=288.98.

A mixture of 2-(5-bromo-2-formyl-4-methoxyphenoxy)acetic acid (3.447 g,11.90 mmol) in acetic anhydride (14.1 mL, 149.0 mmol) at RT is treatedwith sodium acetate (2.935 g, 35.80 mmol) and is then heated at reflux(150° C.), under nitrogen, for 15 h. The RM is allowed to cool to RT,diluted with toluene (50 mL) and treated with 1 M aq. NaOH (100 mL).After stirring at RT for 1 h, the RM is further diluted with water andEtOAc. A subsequent filtration affords6-bromo-5-methoxybenzofuran-2-carboxylic acid as a grey solid that isfurther dried under high vacuum (2.09 g). LC-MS A: t_(R)=0.75 min; noionization. The layers of the filtrate are then separated and theaqueous layer is extracted twice with EtOAc. The combined organic layersare washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=9/1) affords 6-bromo-5-methoxybenzofuran as a colorlesssolid (838 mg, 31%). LC-MS A: t_(R)=0.87 min; no ionization.

A.1.39.6-Chloro-N-(2-(2-fluoro-5-methoxybenzofuran-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(2-fluoro-5-methoxybenzofuran-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.92 min; [M+H]⁺=322.04.

A.1.39.1. 2-(2-Fluoro-5-methoxybenzofuran-6-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(2-fluoro-5-methoxybenzofuran-6-yl)ethyl)carbamate. LC-MS A:t_(R)=0.57 min: [M+H]⁺=210.13.

A.1.39.2. Tert-butyl(2-(2-fluoro-5-methoxybenzofuran-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-2-fluoro-5-methoxybenzofuran. LC-MS A:t_(R)=0.95 min; [M+H]⁺=310.09.

A.1.39.3. 6-Bromo-2-fluoro-5-methoxybenzofuran

A well-stirred mixture of 6-bromo-5-methoxybenzofuran-2-carboxylic acid(1.60 g, 5.90 mmol, preparation described in A.1.38.3.),1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (3.30 g, 8.85 mmol) and sodium hydrogencarbonate(1.438 g, 17.10 mmol) in EtOAc (18 mL) and water (18 mL) is heated to50° C. for 3 h. A second addition of Selectfluor (3.30 g, 8.85 mmol) isthen performed and the RM is further stirred at 50° C. for 2.5 h. The RMis allowed to cool to RT, diluted with EtOAc and treated with 1 M aq.NaOH. After filtration over celite and separation of the layers, theorganic layer is washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=9/1) affords 6-bromo-2-fluoro-5-methoxybenzofuran as ayellow oil (240 mg, 17%). LC-MS A: t_(R)=0.91 min; no ionization.

A.1.40.6-Chloro-N-(2-(6-methoxy-4-methylbenzofuran-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(6-methoxy-4-methylbenzofuran-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.04 min; [M+H]⁺=318.06.

A.1.40.1. 2-(6-Methoxy-4-methylbenzofuran-5-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-methoxy-4-methylbenzofuran-5-yl)ethyl)carbamate. LC-MS B:t_(R)=0.59 min; [M+H]⁺=206.13.

A.1.40.2. Tert-butyl(2-(6-methoxy-4-methylbenzofuran-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-6-methoxy-4-methylbenzofuran. LC-MS B:t_(R)=1.06 min; [M+H]⁺=305.98.

A.1.40.3. 5-Bromo-6-methoxy-4-methylbenzofuran

The title compound is prepared according to the procedure describedabove in A.1.36.3. using3-bromo-6-hydroxy-4-methoxy-2-methylbenzaldehyde. LC-MS B: t_(R)=1.02min; no ionization.

A.1.40.4. 3-Bromo-6-hydroxy-4-methoxy-2-methylbenzaldehyde

A solution of 2-hydroxy-4-methoxy-6-methylbenzaldehyde (3.90 g, 23.50mmol) in anh. MeCN (75 mL) is treated with p-toluenesulfonic acidmonohydrate (228 mg, 1.18 mmol) and the mixture is stirred at RT for 15min. N-bromosuccinimide (4.18 g, 23.50 mmol) is then added portionwiseand the RM is stirred at RT for 15 h. Et₂O and 10% aq. sodiumthiosulfate are added to the RM and the layers are separated. Theorganic layer is successively washed with 10% aq. sodium thiosulfate andwater, dried over anh. MgSO₄, filtered and concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=9/1) affords3-bromo-6-hydroxy-4-methoxy-2-methylbenzaldehyde as a colorless solid(4.10 g, 71%). LC-MS B: t_(R)=0.93 min: [M+H]⁺=245.07.

A.1.40.5. 2-Hydroxy-4-methoxy-6-methylbenzaldehyde

A solution of 2,4-dihydroxy-6-methylbenzaldehyde (4.01 g, 25.80 mmol) inanh. acetone (180 mL) is treated with potassium carbonate (3.57 g, 25.80mmol) and iodomethane (24.2 mL, 387.0 mmol), and the RM is stirred at RTfor 15 h. Water and EtOAc are added and the layers are separated. Theaqueous layer is further extracted with EtOAc and the combined organiclayers are then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC(heptane/EtOAc=9/1) affords 2-hydroxy-4-methoxy-6-methylbenzaldehyde asa colorless solid (3.90 g, 91%). LC-MS B: t_(R)=0.86 min; [M+H]⁺=167.03.

A.1.41. N-(2-(1H-Indol-6-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1H-indol-6-yl)ethan-1-amine. LC-MS A:t_(R)=0.81 min; [M+H]⁺=273.09.

A.1.41.1. 2-(1H-Indol-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 1H-indole-6-carbaldehyde. LC-MS A: t_(R)=0.46min; [M+H]⁺=161.19.

A.1.42. N-(2-(1H-Indol-5-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1H-indol-5-yl)ethan-1-amine. LC-MS A:t_(R)=0.81 min; [M+H]⁺=273.05.

A.1.42.1. 2-(1H-Indol-5-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 1H-indole-5-carbaldehyde. LC-MS A: t_(R)=0.40min; [M+H]⁺=161.46.

A.1.43. 6-Chloro-N-(2-(1-methyl-1H-indol-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1-methyl-1H-indol-6-yl)ethan-1-amine. LC-MS A:t_(R)=0.87 min; [M+H]⁺=287.08.

A.1.43.1. 2-(1-Methyl-1H-indol-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 1-methyl-1H-indole-6-carbaldehyde. LC-MS A:t_(R)=0.51 min; [M+H]⁺=175.35.

A.1.44. 6-Chloro-N-(2-(1-methyl-1H-indol-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1-methyl-1H-indol-5-yl)ethan-1-amine. LC-MS A:t_(R)=0.88 min; [M+H]⁺=287.14.

A.1.44.1. 2-(1-Methyl-1H-indol-5-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 1-methyl-1H-indole-5-carbaldehyde. LC-MS A:t_(R)=0.51 min: [M+H]⁺=175.36.

A.1.45. 6-Chloro-N-(2-(1-ethyl-1H-indol-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1-ethyl-1H-indol-6-yl)ethan-1-amine. LC-MS A:t_(R)=0.91 min; [M+H]⁺=301.10.

A.1.45.1. 2-(1-Ethyl-1H-indol-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 1-ethyl-1H-indole-6-carbaldehyde. LC-MS A:t_(R)=0.55 min; [M+H]⁺=189.27.

A.1.46.6-Chloro-N-(2-(1,3-dimethyl-1H-indol-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1,3-dimethyl-1H-indol-5-yl)ethan-1-amine. LC-MSA: t_(R)=0.92 min; [M+H]⁺=301.08.

A.1.46.1. 2-(1,3-Dimethyl-1H-indol-5-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 1,3-dimethyl-1H-indole-5-carbaldehyde. LC-MS A:t_(R)=0.55 min; [M+H]⁺=189.20.

A.1.46.2. 1,3-Dimethyl-1H-indole-5-carbaldehyde

To a cooled (−78° C.) solution of 5-bromo-1,3-dimethyl-1H-indole (1.31g, 5.85 mmol) in anh. THE (60 mL) is added a solution of BuLi (2.5 M inhexanes, 2.45 mL, 6.12 mmol) and the RM is further stirred at −78° C.,under nitrogen, for 4 min. Anh. DMF (641 mg, 8.77 mmol) is then added tothe previous mixture and stirring at −50° C. is continued for 20 min.The RM is treated with sat. aq. NH₄Cl and is allowed to warm-up to RT.Water and Et₂O are then added and the layers are separated. The aq.layer is further extracted with Et₂O and the combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (heptane/EtOAc=4/1) affords1,3-dimethyl-1H-indole-5-carbaldehyde as a yellow oil (0.56 g, 55%).LC-MS A: t_(R)=0.81 min; [M+H]⁺=174.27.

A.1.46.3. 5-Bromo-1,3-dimethyl-1H-indole

To a solution of 5-bromo-3-methyl-1H-indole (2.00 g, 9.52 mmol) in anh.DMF (15 mL) is added portionwise sodium hydride (60% dispersion inmineral oil, 419 mg, 10.47 mmol) and the RM is further stirred at RT,under nitrogen, for 30 min. Iodomethane (1.2 mL, 19.27 mmol) is thenadded dropwise to the previous mixture and stirring at RT is continuedfor 1.5 h. The cooled (0° C.) RM is treated with water and is allowed towarm-up to RT. The RM is then extracted three times with Et₂O and thecombined organic layers are washed with water, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(heptane/DCM=1/1) affords 5-bromo-1,3-dimethyl-1H-indole as a paleyellow oil (1.86 g, 87%). LC-MS A: t_(R)=0.94 min; [M+H]⁺=224.07.

A.1.47.6-chloro-N-(2-(6-fluoro-1-methyl-1H-indol-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(6-fluoro-1-methyl-1H-indol-5-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.90 min: [M+H]⁺=305.01.

A.1.47.1. 2-(6-Fluoro-1-methyl-1H-indol-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-fluoro-1-methyl-1H-indol-5-yl)ethyl)carbamate. LC-MS A: t_(R)=0.52min; [M+H]⁺=193.21.

A.1.47.2. Tert-butyl (2-(6-fluoro-1-methyl-1H-indol-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-6-fluoro-1-methyl-1H-indole. LC-MS A:t_(R)=0.92 min; [M+H]⁺=293.15.

A.1.47.3. 5-Bromo-6-fluoro-1-methyl-1H-indole

The title compound is prepared according to the procedure describedabove in A.1.46.3. using 5-bromo-6-fluoro-1H-indole. LC-MS A: t_(R)=0.91min; [M+H]⁺=227.93.

A.1.48. N-(2-(Benzo[d]thiazol-6-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzo[d]thiazol-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.79 min; [M+H]⁺=291.01.

A.1.48.1. 2-(Benzo[d]thiazol-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(benzo[d]thiazol-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.43 min;[M+H]⁺=179.24.

A.1.48.2. Tert-butyl (2-(benzo[d]thiazol-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 6-bromobenzo[d]thiazole. LC-MS A: t_(R)=0.83min; [M+H]⁺=279.16.

A.1.49. N-(2-(Benzo[d]thiazol-5-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzo[d]thiazol-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=0.85 min; [M+H]⁺=290.97.

A.1.49.1. 2-(Benzo[d]thiazol-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(benzo[d]thiazol-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.44 min;[M+H]⁺=179.22.

A.1.49.2. Tert-butyl (2-(benzo[d]thiazol-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 5-bromobenzo[d]thiazole. LC-MS B: t_(R)=0.89min; [M+H]⁺=279.08.

A.1.50. N-(2-(Benzo[d]oxazol-6-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzo[d]oxazol-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.76 min; [M+H]⁺=275.06.

A.1.50.1. 2-(Benzo[d]oxazol-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(benzo[d]oxazol-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.39 min:[M+H]⁺=163.51.

A.1.50.2. Tert-butyl (2-(benzo[d]oxazol-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 6-bromobenzo[d]oxazole. LC-MS A: t_(R)=0.81 min;[M+H]⁺=263.19.

A.1.51. N-(2-(Benzo[d]isothiazol-5-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzo[d]isothiazol-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=0.89 min; [M+H]⁺=290.96.

A.1.51.1. 2-(Benzo[d]isothiazol-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(benzo[d]isothiazol-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.46 min;[M+H]⁺=179.21.

A.1.51.2. Tert-butyl (2-(benzo[d]isothiazol-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 5-bromobenzo[d]isothiazole. LC-MS B: t_(R)=0.93min; [M+H]⁺=279.08.

A.1.52.6-Chloro-N-(2-(5-methoxy-1-methyl-1H-indazol-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(5-methoxy-1-methyl-1H-indazol-6-yl)ethan-1-amine hydrochloride. LC-MSA: t_(R)=0.83 min; [M+H]⁺=318.03.

A.1.52.1. 2-(5-Methoxy-1-methyl-1H-indazol-6-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(5-methoxy-1-methyl-1H-indazol-6-yl)ethyl)carbamate. LC-MS A:t_(R)=0.49 min; [M+H]⁺=206.16.

A.1.52.2. Tert-butyl(2-(5-methoxy-1-methyl-1H-indazol-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-5-methoxy-1-methyl-1H-indazole. LC-MS A:t_(R)=0.86 min; [M+H]⁺=306.02.

A.1.52.3. 6-Bromo-5-methoxy-1-methyl-1H-indazole

To a solution of 6-bromo-1-methyl-1H-indazol-5-ol (1.00 g, 4.27 mmol) inanh. DMF (21 mL) at RT are added cesium carbonate (1.67 g, 5.13 mmol)and iodomethane (0.537 mL, 8.54 mmol) and the RM is stirred at RT, undernitrogen, for 45 min. Water and DCM are added and the layers areseparated. The aqueous layer is extracted twice with DCM and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure affording6-bromo-5-methoxy-1-methyl-1H-indazole as a pink solid (1.00 g, 98%).LC-MS A: t_(R)=0.81 min; [M+H]⁺=241.04.

A.1.53. 6-Chloro-N-(2-(5-fluoroquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(5-fluoroquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.67 min; [M+H]⁺=303.02.

A.1.53.1. 2-(5-Fluoroquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(5-fluoroquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.35 min:[M+H]⁺=191.23.

A.1.53.2. Tert-butyl (2-(5-fluoroquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-5-fluoroquinoline. LC-MS A: t_(R)=0.71min; [M+H]⁺=291.10.

A.1.54. 6-Chloro-N-(2-(7-fluoroquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(7-fluoroquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.60 min; [M+H]⁺=303.02.

A.1.54.1. 2-(7-Fluoroquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-fluoroquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.28 min;[M+H]⁺=191.22.

A.1.54.2. Tert-butyl (2-(7-fluoroquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-7-fluoroquinoline. LC-MS A: t_(R)=0.64min; [M+H]⁺=291.10.

A.1.55. 6-Chloro-N-(2-(5,7-difluoroquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(5,7-difluoroquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.78 min; [M+H]⁺=321.01.

A.1.55.1. 2-(5,7-Difluoroquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(5,7-difluoroquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.43 min;[M+H]⁺=209.11.

A.1.55.2. Tert-butyl (2-(5,7-difluoroquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-5,7-difluoroquinoline. LC-MS A:t_(R)=0.82 min; [M+H]⁺=309.08.

A.1.56. 6-Chloro-N-(2-(5,8-difluoroquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(5,8-difluoroquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.80 min; [M+H]⁺=321.02.

A.1.56.1. 2-(5,8-Difluoroquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(5,8-difluoroquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.45 min;[M+H]⁺=209.13.

A.1.56.2. Tert-butyl (2-(5,8-difluoroquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-5,8-difluoroquinoline. LC-MS A:t_(R)=0.84 min; [M+H]⁺=309.11.

A.1.57. 6-Chloro-N-(2-(7-methylquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(7-methylquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.57 min: [M+H]⁺=299.04.

A.1.57.1. 2-(7-Methylquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-methylquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.26 min;[M+H]⁺=187.19.

A.1.57.2. Tert-butyl (2-(7-methylquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-7-methylquinoline. LC-MS A: t_(R)=0.59min; [M+H]⁺=287.16.

A.1.58.6-Chloro-N-(2-(4-chloro-7-methylquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(4-chloro-7-methylquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.74 min; [M+H]⁺=332.99.

A.1.58.1. 2-(4-Chloro-7-methylquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(4-chloro-7-methylquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.43min; [M+H]⁺=221.04.

A.1.58.2. Tert-butyl (2-(4-chloro-7-methylquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-4-chloro-7-methylquinoline. LC-MS A:t_(R)=0.78 min; [M+H]⁺=321.05.

A.1.59.6-Chloro-N-(2-(7-chloro-8-methylquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(7-chloro-8-methylquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.76 min; [M+H]⁺=333.01.

A.1.59.1. 2-(7-Chloro-8-methylquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-chloro-8-methylquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.44min; [M+H]⁺=221.06.

A.1.59.2. Tert-butyl (2-(7-chloro-8-methylquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-7-chloro-8-methylquinoline. LC-MS A:t_(R)=0.79 min; [M+H]⁺=321.05.

A.1.60.6-Chloro-N-(2-(7-chloro-8-fluoroquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(7-chloro-8-fluoroquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.82 min; [M+H]⁺=336.96.

A.1.60.1. 2-(7-Chloro-8-fluoroquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-chloro-8-fluoroquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.49min; [M+H]⁺=225.13.

A.1.60.2. Tert-butyl (2-(7-chloro-8-fluoroquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-7-chloro-8-fluoroquinoline. LC-MS A:t_(R)=0.86 min: [M+H]⁺=325.08.

A.1.61. 6-Chloro-N-(2-(7-fluoroisoquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(7-fluoroisoquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.56 min; [M+H]⁺=303.03.

A.1.61.1. 2-(7-Fluoroisoquinolin-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-fluoroisoquinolin-6-yl)ethyl)carbamate. LC-MS A: t_(R)=0.23 min;[M+H]⁺=191.22.

A.1.61.2. Tert-butyl (2-(7-fluoroisoquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-7-fluoroisoquinoline. LC-MS A:t_(R)=0.60 min; [M+H]⁺=291.15.

A.1.62. 6-Chloro-N-(2-(6-fluoroisoquinolin-7-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(6-fluoroisoquinolin-7-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.55 min; [M+H]⁺=303.04.

A.1.62.1. 2-(6-Fluoroisoquinolin-7-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-fluoroisoquinolin-7-yl)ethyl)carbamate. LC-MS A: t_(R)=0.21 min;[M+H]⁺=191.18.

A.1.62.2. Tert-butyl (2-(6-fluoroisoquinolin-7-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 7-bromo-6-fluoroisoquinoline. LC-MS A:t_(R)=0.60 min; [M+H]⁺=291.12.

A.1.63. 6-Chloro-N-(2-(8-methylquinolin-7-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(8-methylquinolin-7-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.57 min; [M+H]⁺=299.08.

A.1.63.1. 2-(8-Methylquinolin-7-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(8-methylquinolin-7-yl)ethyl)carbamate. LC-MS A: t_(R)=0.28 min;[M+H]⁺=187.27.

A.1.63.2. Tert-butyl (2-(8-methylquinolin-7-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 7-bromo-8-methylquinoline. LC-MS A: t_(R)=0.60min; [M+H]⁺=287.17.

A.1.64.6-Chloro-N-(2-(4,5-difluoro-7-methoxy-2-methylbenzofuran-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(4,5-difluoro-7-methoxy-2-methylbenzofuran-6-yl)ethan-1-amine. LC-MSA: t_(R)=0.98 min; [M+H]⁺=353.95.

A.1.64.1.2-(4,5-Difluoro-7-methoxy-2-methylbenzofuran-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using4,5-difluoro-7-methoxy-2-methylbenzofuran-6-carbaldehyde. LC-MS A:t_(R)=0.63 min: [M+H]⁺=242.02.

A.1.64.2. 4,5-Difluoro-7-methoxy-2-methylbenzofuran-6-carbaldehyde

To a cooled (0° C.) solution of4,5-difluoro-7-methoxy-2-methylbenzofuran (1.482 g, 7.48 mmol) in anh.DCM (15 mL) is added dropwise tin(IV) chloride (1.75 mL, 15.00 mmol) andthe mixture is further stirred at 0° C., under nitrogen, for 15 min.Dichloromethyl methyl ether (0.828 mL, 8.97 mmol) is then added and themixture is stirred at RT, under nitrogen, for 3 h. This formylation ledto the formation of target4,5-difluoro-7-methoxy-2-methylbenzofuran-6-carbaldehyde and isomeric4,5-difluoro-7-methoxy-2-methylbenzofuran-3-carbaldehyde. The resultingRM is then poured onto ice-water (50 mL) and 1 M aq. HCl (20 mL) isadded. The layers are separated and the aq. layer is extracted twicewith DCM. The combined organic layers are dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane/DCM=7/3 to heptane/DCM=3/7) affords4,5-difluoro-7-methoxy-2-methylbenzofuran-6-carbaldehyde as a colorlesssolid. LC-MS A: t_(R)=0.87 min; [M+H]⁺=227.06.

A.1.64.3. 4,5-Difluoro-7-methoxy-2-methylbenzofuran

To a solution of 2,3-difluoro-6-hydroxy-5-methoxybenzaldehyde (5.35 g,28.40 mmol) in anh. DMF (25 mL) at RT are added successively ethyl2-bromopropanoate (3.69 mL, 28.40 mmol), potassium carbonate (4.127 g,29.90 mmol) and potassium iodide (236 mg, 1.42 mmol). The RM is heatedto 80° C., under nitrogen, for 1 h. The RM is then allowed to cool toRT. Water and Et₂O are added and the layers are separated. The aq. layeris extracted twice with Et₂O and the combined organic layers are washedwith water, dried over anh. MgSO₄, filtered and concentrated underreduced pressure giving ethyl2-(3,4-difluoro-2-formyl-6-methoxyphenoxy)propanoate as a yellow solid(5.66 g, 69%). LC-MS A: t_(R)=0.88 min; [M+H]⁺=289.13

To a solution of ethyl2-(3,4-difluoro-2-formyl-6-methoxyphenoxy)propanoate (5.66 g, 17.30mmol) in MeOH (90 mL) and water (23 mL) at RT is added 1 M aq. NaOH(19.0 mL, 19.0 mmol) and the RM is heated to 50° C., under nitrogen, for3 h. The RM is then allowed to cool to RT and is treated with 1 M aq.HCl (19.0 mL). MeOH is removed under reduced pressure and the residualaqueous mixture is extracted twice with DCM. The combined organic layersare washed with water, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure affording2-(3,4-difluoro-2-formyl-6-methoxyphenoxy)propanoic acid as a yellowsolid (6.05 g, quantitative). LC-MS A: t_(R)=0.72 min; [M+H]⁺=261.12.

A mixture of 2-(3,4-difluoro-2-formyl-6-methoxyphenoxy)propanoic acid(6.05 g, 17.30 mmol) in acetic anhydride (19.80 mL, 209.00 mmol) at RTis treated with sodium acetate (4.12 g, 50.20 mmol) and is then heatedat reflux (150° C.), under nitrogen, for 16 h. The RM is allowed to coolto RT, diluted with toluene (35 mL) and treated with 1 M aq. NaOH (60mL). After stirring at RT for 1 h, the RM is diluted with water andextracted twice with EtOAc. The combined organic layers are washedsuccessively with water and brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=8/2) affords 4,5-difluoro-7-methoxy-2-methylbenzofuran asa colorless oil (1.482 g, 43%). LC-MS A: t_(R)=0.91 min: no ionization.

A.1.64.4. 2,3-Difluoro-6-hydroxy-5-methoxybenzaldehyde

To a cooled (−78° C.) solution of 2,3-difluoro-5,6-dimethoxybenzaldehyde(4.72 g, 21.70 mmol) in anh. DCM (50 mL) is added dropwise a solution ofboron trichloride (1 M in DCM, 23.90 mL, 23.90 mmol) and the RM isstirred at RT, under nitrogen, for 15 h. The RM is then cooled to 0° C.,treated dropwise with water (40 mL), and is further stirred at RT for1.5 h. Water and DCM are added and the layers are separated. The aqueouslayer is extracted twice with DCM and the combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure affording2,3-difluoro-6-hydroxy-5-methoxybenzaldehyde as a yellow solid (4.38 g,quantitative). LC-MS A: t_(R)=0.74 min; no ionization.

A.1.64.5. 2,3-Difluoro-5,6-dimethoxybenzaldehyde

To a cooled (−78° C.) solution of 1,2-difluoro-4,5-dimethoxybenzene(4.00 g, 23.00 mmol) in anh. THE (80 mL) is added a solution of BuLi(2.5 M in hexanes, 10.10 mL, 25.25 mmol) and the RM is further stirredat −78° C., under nitrogen, for 1 h. Anh. DMF (2.67 mL, 34.50 mmol) isthen added to the previous mixture and stirring at −78° C. is continuedfor 1 h. The RM is then treated dropwise with sat. aq. NH₄Cl (50 mL) andis allowed to warm-up to RT. Water (50 mL) and EtOAc (100 mL) are thenadded and the layers are separated. The aq. layer is further extractedwith EtOAc (100 mL) and the combined organic layers are washed withwater, dried over anh. MgSO₄, filtered and concentrated under reducedpressure affording 2,3-difluoro-5,6-dimethoxybenzaldehyde as a yellowsolid (4.72 g, quantitative). LC-MS A: t_(R)=0.77 min; [M+H]+=203.08.

A.1.65.6-Chloro-N-(2-(4-fluoro-7-methoxy-2-methylbenzo[b]thiophen-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(4-fluoro-7-methoxy-2-methylbenzo[b]thiophen-6-yl)ethan-1-amine. LC-MSA: t_(R)=0.98 min; [M+H]⁺=352.07.

A.1.65.1.2-(4-Fluoro-7-methoxy-2-methylbenzo[b]thiophen-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using4-fluoro-7-methoxy-2-methylbenzo[b]thiophene-6-carbaldehyde. LC-MS A:t_(R)=0.63 min; [M+H]⁺=240.12.

A.1.65.2. 4-Fluoro-7-methoxy-2-methylbenzo[b]thiophene-6-carbaldehyde

To a cooled (0° C.) solution of4-fluoro-7-methoxy-2-methylbenzo[b]thiophene (3.75 g, 19.10 mmol) inanh. DCM (45 mL) is added dropwise tin(IV) chloride (4.47 mL, 38.20mmol) and the mixture is further stirred at 0° C., under nitrogen, for15 min. Dichloromethyl methyl ether (2.12 mL, 22.90 mmol) is then addedand the mixture is stirred at RT, under nitrogen, for 1 h. Thisformylation led to the formation of target4-fluoro-7-methoxy-2-methylbenzo[b]thiophene-6-carbaldehyde and isomeric4-fluoro-7-methoxy-2-methylbenzo[b]thiophene-3-carbaldehyde (1:1 ratio).The resulting RM is then poured onto ice-water (200 mL) and 1 M aq. HCl(50 mL) is added. The layers are separated and the aq. layer isextracted twice with DCM. The combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane/DCM=4/1 to heptane/DCM=3/7) affords4-fluoro-7-methoxy-2-methylbenzo[b]thiophene-6-carbaldehyde as a paleyellow solid. LC-MS A: t_(R)=0.91 min: [M+H]⁺=225.11.

A.1.65.3. 4-Fluoro-7-methoxy-2-methylbenzo[b]thiophene

To a solution of 5-fluoro-2-methoxybenzenethiol (4.77 g, 30.20 mmol) inanh. acetone (50 mL) are added successively potassium carbonate (5.472g, 39.20 mmol) and 2,3-dichloroprop-1-ene (2.84 mL, 30.20 mmol). The RMis heated at reflux (60° C.), under nitrogen, for 2 h. The RM is thenallowed to cool to RT and is concentrated under reduced pressure. EtOAc(100 mL) and water (100 mL) are added and the layers are separated. Theaq. layer is extracted twice with EtOAc and the combined organic layersare washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure giving(2-chloroallyl)(5-fluoro-2-methoxyphenyl)sulfane as a pale yellow oil(8.00 g, quantitative). LC-MS A: t_(R)=0.93 min; no ionization

A solution of the crude (2-chloroallyl)(5-fluoro-2-methoxyphenyl)sulfaneobtained above (8.00 g, 30.20 mmol) in N,N-diethylaniline (90 mL) isheated to 185° C., under nitrogen, for 48 h. The resulting RM is thenallowed to cool to RT, diluted with EtOAc (300 mL) and washed with 1 Maq. HCl (4×150 mL). The organic layer is then dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane/EtOAc=19/1 to heptane/EtOAc=1/1) affords4-fluoro-7-methoxy-2-methylbenzo[b]thiophene as a yellow oil (3.75 g,63%). LC-MS A: t_(R)=0.94 min; no ionization.

A.1.66. 6-Chloro-N-(2-(chroman-7-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(chroman-7-yl)ethan-1-amine hydrochloride. LC-MSA: t_(R)=0.87 min; [M+H]⁺=290.01.

A.1.66.1. 2-(Chroman-7-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl (2-(chroman-7-yl)ethyl)carbamate.LC-MS A: t_(R)=0.50 min; [M+H]⁺=178.31.

A.1.66.2. Tert-butyl (2-(chroman-7-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 7-bromochromane. LC-MS A: t_(R)=0.90 min; noionization.

A.1.67.6-Chloro-N-(2-(8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-amine.LC-MS A: t_(R)=0.85 min; [M+H]⁺=336.13.

A.1.67.1.2-(8-Methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-carbaldehyde. LC-MS A:t_(R)=0.49 min; [M+H]⁺=223.97.

A.1.68.6-Chloro-N-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine. LC-MS C:t_(R)=0.68 min: [M+H]⁺=292.11.

A.1.68.1. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde.LC-MS C: t_(R)=0.35 min; [M+H]⁺=180.29.

A.1.69.6-Chloro-N-(2-(7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine. LC-MS B:t_(R)=0.92 min; [M+H]⁺=321.97.

A.1.69.1. 2-(7-Methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. LC-MS B:t_(R)=0.50 min; [M+H]⁺=210.32.

A.1.70.6-Chloro-N-(2-(7-ethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(7-ethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine. LC-MS B:t_(R)=0.97 min; [M+H]⁺=336.10.

A.1.70.1. 2-(7-Ethoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using7-ethoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. LC-MS B:t_(R)=0.54 min; [M+H]⁺=223.94.

A.1.70.2. 7-Ethoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde

A solution of 7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde(730 mg, 4.05 mmol) in anh. DMF (20 mL) is treated at RT with cesiumcarbonate (1.584 g, 4.86 mmol) and iodoethane (0.358 mL, 4.46 mmol) andthe RM is stirred at RT, under nitrogen, for 15 h. Water is added andthe mixture is extracted three times with Et₂O. The combined organiclayers are then washed twice with water, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC(heptane/EtOAc=4/1) affords7-ethoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde as a yellowsolid (800 mg, 95%). LC-MS B: t_(R)=0.86 min; [M+H]⁺=209.19.

A.1.70.3. 7-Hydroxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde

A suspension of aluminum chloride (2.372 g, 17.60 mmol) in anh. DCM (25mL) is treated at RT with a solution of7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (1.000 g, 4.89mmol) in anh. DCM (20 mL) and the RM is stirred at RT, under nitrogen,for 2 h. 1 M aq. HCl is then added and the layers are separated. Theaqueous layer is extracted twice with DCM and the combined organiclayers are then dried over anh. MgSO₄, filtered and concentrated underreduced pressure affording7-hydroxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde as a beigesolid (730 mg, 83%). LC-MS B: t_(R)=0.74 min; [M+H]⁺=181.25.

A.1.71.6-Chloro-N-(2-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine. LC-MS A:t_(R)=0.85 min: [M+H]⁺=305.95.

A.1.71.1. 2-(7-Methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. LC-MS A:t_(R)=0.50 min; [M+H]⁺=194.22.

A.1.72.6-Chloro-N-(2-(7-(methylthio)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(7-(methylthio)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine.LC-MS A: t_(R)=0.88 min; [M+H]⁺=337.97.

A.1.72.1.2-(7-(Methylthio)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using7-(methylthio)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. LC-MS A:t_(R)=0.52 min; [M+H]⁺=226.01.

A.1.73.6-Chloro-N-(2-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(8-chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine. LC-MS B:t_(R)=0.97 min; [M+H]⁺=326.04.

A.1.73.1. 2-(8-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using8-chloro-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. LC-MS B:t_(R)=0.51 min; [M+H]⁺=214.13.

A.1.74.6-Chloro-N-(2-(8-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(8-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine. LC-MS B:t_(R)=0.94 min; [M+H]⁺=306.00.

A.1.74.1. 2-(8-Methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using8-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. LC-MS B:t_(R)=0.50 min; [M+H]⁺=194.27.

A.1.74.2. 8-Methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde

A mixture of 8-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde(2.00 g, 7.82 mmol) and Cs₂CO₃ (7.718 g, 23.50 mmol) in DMF (18 mL) isdegassed with nitrogen. Pd(PPhs)₄ (903 mg, 0.78 mmol) and2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.021 g, 8.13 mmol) arethen added and the mixture is degassed again with nitrogen. The RM isthen heated to 90° C., under nitrogen, overnight. The RM is allowed tocool to RT, and diluted with Et₂O and water. The layers are separatedand the aqueous layer is extracted twice with Et₂O. The combined organiclayers are then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords8-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde as a colorlessoil (1.120 g, 80%). LC-MS B: t_(R)=0.81 min; [M+H]⁺=179.25.

A.1.75.6-Chloro-N-(2-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=0.91 min: [M+H]⁺=310.10.

A.1.75.1. 2-(8-Fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate. LC-MSB: t_(R)=0.49 min; [M+H]⁺=198.13.

A.1.75.2. Tert-butyl(2-(8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine. LC-MS B: t_(R)=0.97min; no ionization.

A.1.75.3. 7-Bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine

To a solution of 5-bromo-3-fluorobenzene-1,2-diol (500 mg, 2.29 mmol) inanh. DMF (7 mL) at RT are added potassium carbonate (634 mg, 4.59 mmol)and 1,2-dibromoethane (0.242 mL, 2.75 mmol) and the RM is heated to 100°C. for 2 h. The RM is then allowed to cool to RT, water and Et₂O areadded and the layers are separated. The aqueous layer is extracted twicewith Et₂O and the combined organic layers are washed with water, driedover anh. MgSO₄, filtered and concentrated under reduced pressureaffording 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine as acolorless solid (323 mg, 61%). LC-MS B: t_(R)=0.96 min; no ionization.

A.1.76.7-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile

Tert-butyl(6-chloropyrimidin-4-yl)(2-(7-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate(900 mg, 2.16 mmol) is treated with 4 M HCl in dioxane (10 mL, 40.00mmol) and the RM is stirred at RT for 5 h. The RM is then concentratedunder reduced pressure and the residue is partitioned between DCM andsat. aq. NaHCO₃. The aqueous layer is extracted with DCM and thecombined organic layers are dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toEtOAc) affords7-(2-((6-chloropyrimidin-4-yl)amino)ethyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrileas a yellow solid (630 mg, 92%). LC-MS B: t_(R)=0.88 min; [M+H]⁺=317.08.

A.1.76.1. Tert-butyl(6-chloropyrimidin-4-yl)(2-(7-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

A cooled (15° C.) solution of tert-butyl(2-(7-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate (690 mg,2.27 mmol) in anh. dioxane (22 mL) is treated portionwise with sodiumhydride (60% dispersion in mineral oil, 363 mg, 9.07 mmol) and themixture is stirred at RT, under nitrogen, for 15 min. To the resultingcooled (15° C.) mixture is then added 4,6-dichloropyrimidine (844 mg,5.67 mmol) and heating at 90° C. is continued for 6 h. Water and EtOAcare added and the layers are separated. The organic layer is washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=1/1) affordstert-butyl(6-chloropyrimidin-4-yl)(2-(7-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamateas a yellow solid (900 mg, 95%). LC-MS B: t_(R)=1.15 min; [M+H]⁺=417.04.

A.1.76.2. Tert-butyl(2-(7-cyano-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using7-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile. LC-MS B:t_(R)=0.92 min; [M+H]⁺=305.11.

A.1.76.3. 7-Bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile

A well-stirred suspension of7-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (1.00 g, 4.11mmol) and sodium azide (401 mg, 6.17 mmol) in anh. MeCN (10 mL) istreated at RT with a solution of trifluoromethanesulfonic acid (1.11 mL,12.30 mmol) in anh. MeCN (5 mL). The RM is further stirred at RT, undernitrogen, for 0.5 h. Water is then added and the mixture is filtered.The collected solid is washed with water and is then dissolved in EtOAc.The organic layer is dried over anh. MgSO₄, filtered and concentratedunder reduced pressure affording7-bromo-2,3-dihydrobenzo[b][1,4]dioxine-6-carbonitrile as a pale yellowsolid (920 mg, 93%). LC-MS B: t_(R)=0.89 min; no ionization.

A.1.77. 6-Chloro-N-(2-(chroman-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(chroman-6-yl)ethan-1-amine hydrochloride. LC-MSB: t_(R)=0.94 min; [M+H]⁺=289.90.

A.1.77.1. 2-(Chroman-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl (2-(chroman-6-yl)ethyl)carbamate.LC-MS B: t_(R)=0.49 min; [M+H]⁺=178.26.

A.1.77.2. Tert-butyl (2-(chroman-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromochromane. LC-MS B: t_(R)=0.98 min;[M+H]⁺=278.16.

A.1.78.6-Chloro-N-(2-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-amine. LC-MS A:t_(R)=0.98 min; [M+H]⁺=318.06.

A.1.78.1. 2-(3-Methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using3-methoxy-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde. LC-MS A:t_(R)=0.63 min; [M+H]⁺=206.18.

A.1.79.6-Chloro-N-(2-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=0.61 min; [M+H]⁺=319.09.

A.1.79.1. 2-(7-Methoxy-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)carbamate. LC-MS B:t_(R)=0.32 min: [M+H]⁺=207.42.

A.1.79.2. Tert-butyl(2-(7-methoxy-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-7-methoxy-1,2,3,4-tetrahydroquinoline.LC-MS B: t_(R)=0.64 min; [M+H]⁺=307.15.

A.1.80. N-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-6-chloropyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine. LC-MSB: t_(R)=0.90 min; [M+H]⁺=278.19.

A.1.80.1. 2-(Benzo[d][1,3]dioxol-5-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using benzo[d][1,3]dioxole-5-carbaldehyde. LC-MS B:t_(R)=0.43 min; [M+H]⁺=166.13.

A.1.81.6-Chloro-N-(2-(6-methoxybenzo[d][1,3]dioxol-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(6-methoxybenzo[d][1,3]dioxol-5-yl)ethan-1-amine. LC-MS B: t_(R)=0.93min; [M+H]⁺=308.15.

A.1.81.1. 2-(6-Methoxybenzo[d][1,3]dioxol-5-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using 6-methoxybenzo[d][1,3]dioxole-5-carbaldehyde.LC-MS B: t_(R)=0.49 min; [M+H]⁺=196.29.

A.1.82.6-Chloro-N-(2-(6-(difluoromethoxy)benzo[d][1,3]dioxol-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(6-(difluoromethoxy)benzo[d][1,3]dioxol-5-yl)ethan-1-amine. LC-MS A:t_(R)=0.87 min; [M+H]⁺=343.95.

A.1.82.1. 2-(6-(Difluoromethoxy)benzo[d][1,3]dioxol-5-yl)ethan-1-amine

The title compound is prepared according to the procedure describedabove in A.1.4.1. using6-(difluoromethoxy)benzo[d][1,3]dioxole-5-carbaldehyde. LC-MS A:t_(R)=0.52 min; [M+H]⁺=232.04.

A.1.83.6-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)benzo[d][1,3]dioxole-5-carbonitrile

The title compound is prepared according to the procedure describedabove in A.1.76. using tert-butyl(6-chloropyrimidin-4-yl)(2-(6-cyanobenzo[d][1,3]dioxol-5-yl)ethyl)carbamate.LC-MS A: t_(R)=0.79 min; [M+H]⁺=303.02.

A.1.83.1. Tert-butyl(6-chloropyrimidin-4-yl)(2-(6-cyanobenzo[d][1,3]dioxol-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.76.1. using tert-butyl(2-(6-cyanobenzo[d][1,3]dioxo-5-yl)ethyl)carbamate. LC-MS A: t_(R)=1.01min; [M+H]⁺=403.02.

A.1.83.2. Tert-butyl (2-(6-cyanobenzo[d][1,3]dioxol-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.2.2. using 6-bromobenzo[d][1,3]dioxole-5-carbonitrile.LC-MS A: t_(R)=0.84 min: [M+H]⁺=291.08.

A.1.84.6-Chloro-N-(2-(2,3-dihydrobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(2,3-dihydrobenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=0.98 min; [M+H]⁺=291.98.

A.1.84.1. 2-(2,3-Dihydrobenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(2,3-dihydrobenzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B:t_(R)=0.54 min; [M+H]⁺=180.12.

A.1.84.2. Tert-butyl(2-(2,3-dihydrobenzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-2,3-dihydrobenzo[b]thiophene. LC-MS B:t_(R)=1.01 min; [M+H]⁺=280.14.

A.1.85. 6-Chloro-N-(2-(2,3-dihydro-1H-inden-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(2,3-dihydro-1H-inden-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.04 min; [M+H]⁺=274.03.

A.1.85.1. 2-(2,3-Dihydro-1H-inden-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(2,3-dihydro-1H-inden-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.45 min;no ionization.

A.1.85.2. Tert-butyl (2-(2,3-dihydro-1H-inden-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-2,3-dihydro-1H-indene. LC-MS B:t_(R)=1.09 min; [M+H]⁺=262.13.

A.1.86.6-Chloro-N-(2-(2,3-dihydrobenzofuran-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(2,3-dihydrobenzofuran-6-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=0.92 min; [M+H]⁺=276.28.

A.1.86.1. 2-(2,3-Dihydrobenzofuran-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(2,3-dihydrobenzofuran-6-yl)ethyl)carbamate. LC-MS B: t_(R)=0.45 min;[M+H]⁺=164.07.

A.1.86.2. Tert-butyl (2-(2,3-dihydrobenzofuran-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-2,3-dihydrobenzofuran. LC-MS B:t_(R)=0.99 min; [M+H]⁺=264.10.

A.1.87.6-Chloro-N-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(2,3-dihydrobenzofuran-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=0.89 min; [M+H]⁺=276.06.

A.1.87.1. 2-(2,3-Dihydrobenzofuran-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(2,3-dihydrobenzofuran-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.46 min:[M+H]⁺=164.08.

A.1.87.2. Tert-butyl (2-(2,3-dihydrobenzofuran-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-2,3-dihydrobenzofuran. LC-MS B:t_(R)=0.95 min; no ionization.

A.1.88.6-Chloro-N-(2-(1,3-dihydroisobenzofuran-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(1,3-dihydroisobenzofuran-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=0.85 min; [M+H]⁺=276.01.

A.1.88.1. 2-(1,3-Dihydroisobenzofuran-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.41min; [M+H]⁺=164.08.

A.1.88.2. Tert-butyl (2-(1,3-dihydroisobenzofuran-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-1,3-dihydroisobenzofuran. LC-MS B:t_(R)=0.89 min; no ionization.

A.1.89.6-Chloro-N-(2-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.95 min; [M+H]⁺=347.99.

A.1.89.1. 2-(6-Chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)carbamate. LC-MSA: t_(R)=0.59 min; [M+H]⁺=236.00.

A.1.89.2. Tert-butyl(2-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using5-bromo-6-chloro-2,2-difluorobenzo[d][1,3]dioxole. LC-MS A: t_(R)=0.98min; no ionization.

A.1.90.6-Chloro-N-(2-(6-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(6-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.82 min; [M+H]⁺=324.97.

A.1.90.1.2-(6-Chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)ethyl)carbamate.LC-MS A: t_(R)=0.45 min; [M+H]⁺=213.12.

A.1.90.2. Tert-butyl(2-(6-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using7-bromo-6-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazine. LC-MS A:t_(R)=0.85 min: [M+H]⁺=313.05.

A.1.91.6-Chloro-N-(2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-aminehydrochloride. LC-MS A: t_(R)=0.85 min; [M+H]⁺=323.04.

A.1.91.1.2-(7-Fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethyl)carbamate.LC-MS A: t_(R)=0.49 min; [M+H]⁺=211.15.

A.1.91.2. tert-Butyl(2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using6-bromo-7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine. LC-MS A:t_(R)=0.89 min; [M+H]⁺=311.16.

A.1.91.3. 6-Bromo-7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a cooled (0° C.) suspension of sodium hydride (60% dispersion inmineral oil, 194 mg, 4.84 mmol)) in anh. DMF (15 mL) is added a solutionof 6-bromo-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (1.00 g, 3.72mmol) in anh. DMF (10 mL). The mixture is stirred at 0° C. for 15 min.,and iodomethane (0.937 mL, 14.90 mmol) is then added. The RM is stirredat 0° C. for 15 min., and then at RT overnight. Water and Et₂O are addedand the layers are separated. The aqueous layer is extracted twice withEt₂O and the combined organic layers are washed with water, dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (heptane/DCM=1/1) affords6-bromo-7-fluoro-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine as ayellow oil (311 mg, 34%). LC-MS A: t_(R)=0.89 min; no ionization.

A.1.92.6-(2-((6-Chloropyrimidin-4-yl)amino)ethyl)-7-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-one

The title compound is prepared according to the procedure describedabove in A.1.1. using6-(2-aminoethyl)-7-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-onehydrochloride. LC-MS A: t_(R)=0.81 min; [M+H]⁺=346.94.

A.1.92.1.6-(2-Aminoethyl)-7-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-onehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)carbamate.LC-MS A: t_(R)=0.47 min; [M+H]⁺=235.11.

A.1.92.2. Tert-butyl(2-(7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using6-bromo-7-methoxy-1-methyl-3,4-dihydroquinolin-2(1H)-one. LC-MS A:t_(R)=0.84 min; [M+H]⁺=335.10.

A.1.93.6-Chloro-N-(2-(7-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using2-(7-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-aminehydrochloride.

A.1.93.1.2-(7-Fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(7-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)carbamate.LC-MS A: t_(R)=0.52 min; [M+H]⁺=209.26.

A.1.93.2. Tert-butyl(2-(7-fluoro-1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using6-bromo-7-fluoro-1-methyl-1,2,3,4-tetrahydroquinoline. LC-MS A:t_(R)=0.89 min; [M+H]⁺=309.19.

A.1.93.3. 6-Bromo-7-fluoro-1-methyl-1,2,3,4-tetrahydroquinoline

The title compound is prepared according to the procedure describedabove in A.1.91.3. using 6-bromo-7-fluoro-1,2,3,4-tetrahydroquinoline.

A.1.94.6-Chloro-N-(2-(6-methylbenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(6-methylbenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.02 min; [M+H]⁺=304.11.

A.1.94.1. 2-(6-Methylbenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(6-methylbenzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.58min; [M+H]⁺=192.18.

A.1.94.2. Tert-butyl (2-(6-methylbenzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 5-bromo-6-methylbenzo[b]thiophene. LC-MS B:t_(R)=1.06 min; no ionization.

A.1.94.3. 5-Bromo-6-methylbenzo[b]thiophene

The title compound is prepared according to the procedure describedabove in A.1.31.3. using 5-bromo-6-methylbenzo[b]thiophene-2-carboxylicacid. LC-MS B: t_(R)=1.04 min; no ionization.

A.1.94.4. 5-Bromo-6-methylbenzo[b]thiophene-2-carboxylic acid

The title compound is prepared according to the procedure describedabove in A.1.31.4. using methyl5-bromo-6-methylbenzo[b]thiophene-2-carboxylate. LC-MS B: t_(R)=0.93min; no ionization.

A.1.94.5. Methyl 5-bromo-6-methylbenzo[b]thiophene-2-carboxylate

The title compound is prepared according to the procedure describedabove in A.1.31.5. using 5-bromo-2-fluoro-4-methylbenzaldehyde. LC-MS B:t_(R)=1.08 min; no ionization.

A.1.95.6-Chloro-N-(2-(4-methylbenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(4-methylbenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.01 min: [M+H]⁺=304.11.

A.1.95.1. 2-(4-Methylbenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(4-methylbenzo[b]thiophen-5-yl)ethyl)carbamate. LC-MS B: t_(R)=0.59min; [M+H]⁺=192.29.

A.1.95.2. Tert-butyl (2-(4-methylbenzo[b]thiophen-5-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 4-methylbenzo[b]thiophen-5-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.05 min; no ionization.

A.1.95.3. 4-Methylbenzo[b]thiophen-5-yl trifluoromethanesulfonate

The title compound is prepared according to the procedure describedabove in A.1.20.3. using 4-methylbenzo[b]thiophen-5-ol. LC-MS B:t_(R)=1.09 min; no ionization.

A.1.95.4. 4-Methylbenzo[b]thiophen-5-ol

The title compound is prepared according to the procedure describedabove in A.1.19.4. using 5-(methoxymethoxy)-4-methylbenzo[b]thiophene.LC-MS B: t_(R)=0.82 min; no ionization.

A.1.95.5. 5-(Methoxymethoxy)-4-methylbenzo[b]thiophene

The title compound is prepared according to the procedure describedabove in A.1.19.5. using 4-bromo-5-(methoxymethoxy)benzo[b]thiophene.LC-MS B: t_(R)=0.97 min; [M+H]⁺=209.19.

A.1.95.6. 4-Bromo-5-(methoxymethoxy)benzo[b]thiophene

The title compound is prepared according to the procedure describedabove in A.1.19.6. using 4-bromobenzo[b]thiophen-5-ol. LC-MS B:t_(R)=1.00 min; no ionization.

A.1.95.7. 4-Bromobenzo[b]thiophen-5-ol

A cooled (0° C.) solution of benzo[b]thiophen-5-ol (3.00 g, 19.40 mmol)and diisopropylamine (0.272 mL, 1.94 mmol) in anh. DCM (60 mL) istreated dropwise with a solution of N-bromosuccinimide (3.621 g, 20.30mmol) in anh. DCM (135 mL). The RM is further stirred at 0° C. for 2 h.Water is added and the layers are separated. The organic layer is thenwashed successively with sat. aq. NaHCO₃ and with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords4-bromobenzo[b]thiophen-5-ol as an orange solid (3.13 g, 71%). LC-MS B:t_(R)=0.86 min; no ionization.

A.1.96.6-Chloro-N-(2-(5-methoxybenzo[b]thiophen-6-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(5-methoxybenzo[b]thiophen-6-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.03 min; [M+H]⁺=320.13.

A.1.96.1. 2-(5-Methoxybenzo[b]thiophen-6-yl)ethan-1-amine hydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(5-methoxybenzo[b]thiophen-6-yl)ethyl)carbamate. LC-MS B: t_(R)=0.57min; [M+H]⁺=208.15.

A.1.96.2. Tert-butyl (2-(5-methoxybenzo[b]thiophen-6-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 6-bromo-5-methoxybenzo[b]thiophene. LC-MS B:t_(R)=1.04 min; [M+H]⁺=308.20.

A.1.96.3. 6-Bromo-5-methoxybenzo[b]thiophene

The title compound is prepared according to the procedure describedabove in A.1.31.3. using 6-bromo-5-methoxybenzo[b]thiophene-2-carboxylicacid. LC-MS B: t_(R)=0.98 min; no ionization.

A.1.96.4. 6-Bromo-5-methoxybenzo[b]thiophene-2-carboxylic acid

The title compound is prepared according to the procedure describedabove in A.1.31.4. using methyl6-bromo-5-methoxybenzo[b]thiophene-2-carboxylate. LC-MS B: t_(R)=0.87min; no ionization.

A.1.96.5. Methyl 6-bromo-5-methoxybenzo[b]thiophene-2-carboxylate

The title compound is prepared according to the procedure describedabove in A.1.31.5. using 4-bromo-2-fluoro-5-methoxybenzaldehyde. LC-MSB: t_(R)=1.03 min; no ionization.

A.1.97.6-Chloro-N-(2-(3-ethoxy-1-fluoronaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(3-ethoxy-1-fluoronaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.12 min; [M+H]⁺=346.19.

A.1.97.1. 2-(3-Ethoxy-1-fluoronaphthalen-2-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-ethoxy-1-fluoronaphthalen-2-yl)ethyl)carbamate. LC-MS B:t_(R)=0.71 min; [M+H]⁺=234.26.

A.1.97.2. Tert-butyl(2-(3-ethoxy-1-fluoronaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 3-ethoxy-1-fluoronaphthalen-2-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.13 min; [M+H]⁺=334.23.

A.1.97.3. 3-Ethoxy-1-fluoronaphthalen-2-yl trifluoromethanesulfonate

The title compound is prepared according to the procedure describedabove in A.1.3.3. using 3-ethoxy-1-fluoronaphthalen-2-ol. LC-MS B:t_(R)=1.13 min; no ionization.

A.1.97.4. 3-Ethoxy-1-fluoronaphthalen-2-ol

The title compound is prepared according to the procedure describedabove in A.1.19.4. using3-ethoxy-1-fluoro-2-(methoxymethoxy)naphthalene. LC-MS B: t_(R)=0.91min; no ionization.

A.1.97.5. 3-Ethoxy-1-fluoro-2-(methoxymethoxy)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.20.5. using 1-bromo-3-ethoxy-2-(methoxymethoxy)naphthalene.LC-MS B: t_(R)=1.01 min; [M+H]⁺=251.23.

A.1.97.6. 1-Bromo-3-ethoxy-2-(methoxymethoxy)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.21.5. using 2-ethoxy-3-(methoxymethoxy)naphthalene. LC-MSB: t_(R)=1.07 min; no ionization. ¹H NMR (400 MHz, d6-DMSO) δ: 8.02-8.05(m, 1H), 7.85-7.87 (m, 1H), 7.49-7.51 (m, 3H), 5.25 (s, 2H), 4.21 (q,J=6.9 Hz, 2H), 3.60 (s, 3H), 1.44 (t, J=6.9 Hz, 3H).

A.1.97.7. 2-Ethoxy-3-(methoxymethoxy)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.19.6. using 2-hydroxy-3-ethoxynaphthalene. LC-MS B:t_(R)=0.96 min; [M+H]⁺=233.37

A.1.98.6-chloro-N-(2-(3-ethoxy-1-methylnaphthalen-2-yl)ethyl)pyrimidin-4-amine

The title compound is prepared according to the procedure describedabove in A.1.1. using 2-(3-ethoxy-1-methylnaphthalen-2-yl)ethan-1-aminehydrochloride. LC-MS B: t_(R)=1.10 min; [M+H]⁺=342.31.

A.1.98.1. 2-(3-Ethoxy-1-methylnaphthalen-2-yl)ethan-1-aminehydrochloride

The title compound is prepared according to the procedure describedabove in A.1.1.1. using tert-butyl(2-(3-ethoxy-1-methylnaphthalen-2-yl)ethyl)carbamate. LC-MS B:t_(R)=0.72 min; [M+H]⁺=230.42.

A.1.98.2. Tert-butyl(2-(3-ethoxy-1-methylnaphthalen-2-yl)ethyl)carbamate

The title compound is prepared according to the procedure describedabove in A.1.1.2. using 3-ethoxy-1-methylnaphthalen-2-yltrifluoromethanesulfonate. LC-MS B: t_(R)=1.14 min; [M+H]⁺=330.31.

A.1.98.3. 3-Ethoxy-1-methylnaphthalen-2-yl trifluoromethanesulfonate

The title compound is prepared according to the procedure describedabove in A.1.3.3. using 3-ethoxy-1-methylnaphthalen-2-ol. LC-MS B:t_(R)=1.16 min; [M+H]⁺=335.07.

A.1.98.4. 3-Ethoxy-1-methylnaphthalen-2-ol

The title compound is prepared according to the procedure describedabove in A.1.19.4. using3-ethoxy-1-methyl-2-(methoxymethoxy)naphthalene. LC-MS B: t_(R)=0.97min; [M+H]⁺=202.3.

A.1.98.5. 3-Ethoxy-1-methyl-2-(methoxymethoxy)naphthalene

The title compound is prepared according to the procedure describedabove in A.1.20.5. using 1-bromo-3-ethoxy-2-(methoxymethoxy)naphthalene(A.1.97.6.). LC-MS B: t_(R)=1.07 min; [M+H]⁺=247.34.

A.1.99.6-Chloro-N-(2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

To a solution of 2-(7-fluorobenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride (3.970 g, 17.10 mmol) in 2-propanol (170 mL) at RT areadded TEA (8.35 mL, 60.00 mmol) and 4,6-dichloropyrimidine (3.063 g,20.60 mmol). The mixture is refluxed (90° C.), under nitrogen, for 1.5 hand a second addition of 4,6-dichloropyrimidine (2.547 g, 17.10 mmol) isthen performed. The RM is further refluxed (90° C.), under nitrogen, for4 h and is allowed to cool to RT. The solvent is partially removed underreduced pressure, DCM and water are added and the layers are separated.The aq. layer is extracted twice with DCM and the combined organiclayers are then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (fromheptane/EtOAc=7/3 to EtOAc) affords6-chloro-N-(2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine asa yellow solid (4.96 g, 94%). LC-MS B: t_(R)=0.99 min; [M+H]⁺=308.12.

A.1.99.1. 2-(7-Fluorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

To a solution of tert-butyl(2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate (12.090 g, 40.00 mmol)in DCM (100 mL) is added 4 M HCl in dioxane (100.0 mL, 400.0 mmol) andthe mixture is stirred at RT for 2 h. The RM is then concentrated underreduced pressure affording2-(7-fluorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride as acolorless solid that is further dried under high vacuum (5.030 g, 54%).LC-MS B: t_(R)=0.60 min; [M+H]⁺=196.19.

A.1.99.2. Tert-butyl (2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate

A mixture of 5-bromo-7-fluorobenzo[b]thiophene (10.222 g, 44.20 mmol),potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (12.861g, 48.70 mmol) and cesium carbonate (43.237 g, 133.00 mmol) in toluene(120 mL) and water (40 mL) is degassed three times with nitrogen.Palladium(II) acetate (497 mg, 2.21 mmol) and RuPhos (2.173 g, 4.42mmol) are then added and the mixture is heated to 95° C., undernitrogen, overnight. The RM is allowed to cool to RT, water is added andthe mixture is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords tert-butyl(2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate as a light yellowsolid (12.09 g, 93%). LC-MS B: t_(R)=1.04 min; no ionization.

A.1.99.3. 5-Bromo-7-fluorobenzo[b]thiophene

A mixture of crude 5-bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid(19.350 g, 64.50 mmol) and copper(I) oxide (5.033 g, 35.20 mmol) in DMF(200 mL) is heated to 140° C., under nitrogen, overnight. The RM isallowed to cool to RT and is filtered over celite to remove copper saltsthat are washed with Et₂O. Water and Et₂O are added to the filtrate andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=4/1) affords5-bromo-7-fluorobenzo[b]thiophene as a colorless solid (11.985 g, 80%).LC-MS B: t_(R)=1.02 min; no ionization.

A.1.99.4. 5-Bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid

A mixture of crude methyl5-bromo-7-fluorobenzo[b]thiophene-2-carboxylate (24.140 g, 64.50 mmol)in THE (180 mL), MeOH (23 mL) and water (58 mL) is treated portionwisewith lithium hydroxide (5.998 g, 250.00 mmol). The resulting mixture isstirred at RT for 1 h. The cooled (0° C.) RM is then acidified byaddition of 2 M aq. HCl and the organic solvents are removed underreduced pressure. The resulting suspension is filtered and the obtainedsolid is washed with water and dried under high vacuum to give crude5-bromo-7-fluorobenzo[b]thiophene-2-carboxylic acid as a colorless solid(19.350 g, quantitative). LC-MS B: t_(R)=0.91 min; no ionization.

A.1.99.5. Methyl 5-bromo-7-fluorobenzo[b]thiophene-2-carboxylate

To a cooled (0° C.) mixture of 5-bromo-2,3-difluorobenzaldehyde (15.000g, 64.50 mmol) and potassium carbonate (13.640 g, 96.70 mmol) in DMF(150 mL) is added dropwise methyl 2-mercaptoacetate (7.28 mL, 77.40mmol) and the resulting mixture is stirred at RT for 1 h. The RM is thentreated with water and stirred at RT for 15 min. The resultingsuspension is filtered and the obtained solid is washed with water anddried under high vacuum to give crude methyl5-bromo-7-fluorobenzo[b]thiophene-2-carboxylate as a colorless solid(24.140 g, quantitative). LC-MS B: t_(R)=1.06 min; no ionization.

A.1.100.6-Chloro-N-(2-(7-chlorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

To a solution of 2-(7-chlorobenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride (468 mg, 1.81 mmol) in 2-propanol (20 mL) at RT are addedTEA (0.88 mL, 6.34 mmol) and 4,6-dichloropyrimidine (324 mg, 2.17 mmol).The mixture is refluxed (90° C.), under nitrogen, for 1.5 h. The RM isallowed to cool to RT, DCM and water are added and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to heptane/EtOAc=1/1) affords6-chloro-N-(2-(7-chlorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine asa colorless solid. LC-MS B: t_(R)=1.04 min; [M+H]⁺=324.05.

A.1.100.1. 2-(7-Chlorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

To a solution of tert-butyl(2-(7-chlorobenzo[b]thiophen-5-yl)ethyl)carbamate (568 mg, 1.77 mmol) inDCM (20 mL) is added 4 M HCl in dioxane (4.5 mL, 18.0 mmol) and themixture is stirred at RT overnight. The RM is then concentrated underreduced pressure to afford2-(7-chlorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride as acolorless solid (468 mg, quantitative). LC-MS B: t_(R)=0.62 min;[M+H]⁺=212.10.

A.1.100.2. Tert-butyl(2-(7-chlorobenzo[b]thiophen-5-yl)ethyl)carbamate

A mixture of 5-bromo-7-chlorobenzo[b]thiophene (672 mg, 2.52 mmol),potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (734 mg,2.78 mmol) and cesium carbonate (2.468 g, 7.57 mmol) in toluene (20 mL)and water (7 mL) is degassed three times with nitrogen. Palladium(II)acetate (28.4 mg, 0.12 mmol) and RuPhos (124 mg, 0.25 mmol) are addedand the resulting mixture is heated to 95° C., under nitrogen,overnight. The RM is allowed to cool to RT, water is added and themixture is extracted twice with EtOAc. The combined organic layers arethen washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=4/1) affords tert-butyl(2-(7-chlorobenzo[b]thiophen-5-yl)ethyl)carbamate as a yellow solid (568mg, 72%). LC-MS B: t_(R)=1.06 min; no ionization.

A.1.100.3. 5-Bromo-7-chlorobenzo[b]thiophene

A mixture of 5-bromo-7-chlorobenzo[b]thiophene-2-carboxylic acid (1.004g, 3.41 mmol) and copper(I) oxide (1.903 g, 13.30 mmol) in DMF (17 mL)is heated to 140° C., under nitrogen, overnight. The RM is allowed tocool to RT and is filtered over celite to remove copper salts that arewashed with Et₂O. Water and Et₂O are added to the filtrate and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords5-bromo-7-chlorobenzo[b]thiophene as a colorless solid (672 mg, 80%).LC-MS B: t_(R)=1.05 min; no ionization.

A.1.100.4. 5-Bromo-7-chlorobenzo[b]thiophene-2-carboxylic acid

A mixture of methyl 5-bromo-7-chlorobenzo[b]thiophene-2-carboxylate(1.137 g, 3.61 mmol) in THE (30 mL), MeOH (4 mL) and water (10 mL) istreated portionwise with lithium hydroxide (259 mg, 10.80 mmol). Theresulting mixture is stirred at RT for 1 h. The cooled (0° C.) RM isthen acidified by addition of 2 M aq. HCl and the organic solvents areremoved under reduced pressure. The resulting suspension is filtered andthe obtained solid is washed with water and dried under high vacuum togive 5-bromo-7-chlorobenzo[b]thiophene-2-carboxylic acid as a beigesolid (1.003 g, 95%). LC-MS B: t_(R)=0.95 min; no ionization.

A.1.100.5. Methyl 5-bromo-7-chlorobenzo[b]thiophene-2-carboxylate

To a cooled (0° C.) mixture of 5-bromo-3-chloro-2-fluorobenzaldehyde(1.000 g, 4.13 mmol) and potassium carbonate (873 mg, 6.19 mmol) in DMF(10 mL) is added dropwise methyl 2-mercaptoacetate (0.466 mL, 4.95 mmol)and the resulting mixture is stirred at RT for 1.5 h, and then at 60° C.for 1 h. The RM is treated with water and stirred at RT for 15 min. Theresulting suspension is filtered and the obtained solid is washed withwater and dried under high vacuum to give methyl5-bromo-7-chlorobenzo[b]thiophene-2-carboxylate as a colorless solid(1.137 g, 90%). LC-MS B: t_(R)=1.11 min; no ionization.

A.1.101.6-Chloro-N-(2-(7-methylbenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

To a solution of 2-(7-methylbenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride (1.985 g, 8.72 mmol) in 2-propanol (40 mL) at RT are addedTEA (4.25 mL, 30.50 mmol) and 4,6-dichloropyrimidine (1.558 g, 10.50mmol).

The mixture is refluxed (90° C.), under nitrogen, for 2.5 h. The RM isallowed to cool to RT, DCM and water are added and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to heptane/EtOAc=1/1) affords6-chloro-N-(2-(7-methylbenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine asa colorless solid (2.379 g, 90%). LC-MS B: t_(R)=1.02 min;[M+H]⁺=304.15.

A.1.101.1. 2-(7-Methylbenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

To a solution of tert-butyl(2-(7-methylbenzo[b]thiophen-5-yl)ethyl)carbamate (2.882 g, 9.89 mmol)in DCM (25 mL) is added 4 M HCl in dioxane (25.0 mL, 100.0 mmol) and themixture is stirred at RT for 1 h. The RM is then cooled in an ice bathfor 15 min and the obtained solid is filtered off and further driedunder high vacuum to afford2-(7-methylbenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride as acolorless solid (1.985 g, 88%). LC-MS B: t_(R)=0.60 min; [M+H]⁺=192.30.

A.1.101.2. Tert-butyl(2-(7-methylbenzo[b]thiophen-5-yl)ethyl)carbamate

A mixture of 5-bromo-7-methylbenzo[b]thiophene (2.360 g, 9.91 mmol),potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (2.882 g,10.90 mmol) and cesium carbonate (9.689 g, 29.70 mmol) in toluene (24mL) and water (12 mL) is degassed three times with nitrogen.Palladium(II) acetate (111 mg, 0.49 mmol) and RuPhos (487 mg, 0.99 mmol)are then added and the mixture is heated to 95° C., under nitrogen,overnight. The RM is allowed to cool to RT, water is added and themixture is extracted twice with EtOAc. The combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords tert-butyl(2-(7-methylbenzo[b]thiophen-5-yl)ethyl)carbamate as a yellow solid(2.882 g, 99%). LC-MS B: t_(R)=1.05 min; no ionization.

A.1.101.3. 5-Bromo-7-methylbenzo[b]thiophene

A mixture of 5-bromo-7-methylbenzo[b]thiophene-2-carboxylic acid (3.440g, 12.70 mmol) and copper(I) oxide (1.812 g, 12.70 mmol) in DMF (40 mL)is heated to 140° C., under nitrogen, overnight. The RM is allowed tocool to RT and is filtered over celite to remove copper salts that arewashed with Et₂O. Water and Et₂O are added to the filtrate and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords5-bromo-7-methylbenzo[b]thiophene as a clear oil (2.361 g, 82%). LC-MSB: t_(R)=1.04 min; no ionization.

A.1.101.4. 5-Bromo-7-methylbenzo[b]thiophene-2-carboxylic acid

A mixture of methyl 5-bromo-7-methylbenzo[b]thiophene-2-carboxylate(4.000 g, 13.50 mmol) in THE (60 mL), MeOH (8 mL) and water (20 mL) istreated portionwise with lithium hydroxide (1.002 g, 41.80 mmol). Theresulting mixture is stirred at RT for 1 h. The cooled (0° C.) RM isthen acidified by addition of 2 M aq. HCl and the organic solvents areremoved under reduced pressure. The resulting suspension is filtered andthe obtained solid is washed with water and dried under high vacuum togive crude 5-bromo-7-methylbenzo[b]thiophene-2-carboxylic acid as anoff-white solid (3.442 g, 94%). LC-MS B: t_(R)=0.93 min; no ionization.

A.1.101.5. Methyl 5-bromo-7-methylbenzo[b]thiophene-2-carboxylate

To a cooled (0° C.) suspension of 5-bromo-2-fluoro-3-methylbenzaldehyde(3.000 g, 13.50 mmol) and potassium carbonate (2.865 g, 20.30 mmol) inDMF (25 mL) is added dropwise methyl 2-mercaptoacetate (1.53 mL, 16.30mmol) and the mixture is stirred at RT for 1 h, and then at 60° C. for 3h. The RM is treated with water and stirred at RT for 15 min. Theresulting suspension is filtered and the obtained solid is washed withwater and dried under high vacuum to give crude methyl5-bromo-7-methylbenzo[b]thiophene-2-carboxylate as an off-white solid(4.000 g, quantitative). LC-MS B: t_(R)=1.08 min; no ionization.

A.1.102.6-Chloro-N-(2-(7-fluoro-6-methoxybenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

To a solution of2-(7-fluoro-6-methoxybenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride(0.986 g, 3.77 mmol) in 2-propanol (20 mL) at RT are added TEA (1.84 mL,13.20 mmol) and 4,6-dichloropyrimidine (0.673 g, 4.52 mmol). Theresulting mixture is refluxed (90° C.), under nitrogen, for 1.5 h. TheRM is allowed to cool to RT, DCM and water are added and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to heptane/EtOAc=1/1) affords6-chloro-N-(2-(7-fluoro-6-methoxybenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amineas an off-white solid (1.141 g, 90%). LC-MS B: t_(R)=1.03 min;[M+H]⁺=337.98.

A.1.102.1. 2-(7-Fluoro-6-methoxybenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride

To a solution of tert-butyl(2-(7-fluoro-6-methoxybenzo[b]thiophen-5-yl)ethyl)carbamate (1.398 g,4.28 mmol) in DCM (11 mL) is added 4 M HCl in dioxane (11.0 mL, 44.0mmol) and the mixture is stirred at RT for 1 h. The RM is thenconcentrated to dryness under reduced pressure affording2-(7-fluoro-6-methoxybenzo[b]thiophen-5-yl)ethan-1-amine hydrochlorideas a light yellow solid (0.986 g, 88%). LC-MS B: t_(R)=0.64 min;[M+H]⁺=226.21.

A.1.102.2. Tert-butyl(2-(7-fluoro-6-methoxybenzo[b]thiophen-5-yl)ethyl)carbamate

A mixture of 5-bromo-7-fluoro-6-methoxybenzo[b]thiophene (1.413 g, 5.41mmol), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate(1.573 g, 5.95 mmol) and cesium carbonate (5.289 g, 16.20 mmol) intoluene (24 mL) and water (12 mL) is degassed three times with nitrogen.Palladium(II) acetate (60.8 mg, 0.27 mmol) and RuPhos (266 mg, 0.54mmol) are added and the resulting mixture is heated to 95° C., undernitrogen, overnight. The RM is allowed to cool to RT, water is added andthe mixture is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords tert-butyl(2-(7-fluoro-6-methoxybenzo[b]thiophen-5-yl)ethyl)carbamate as a lightyellow solid (1.398 g, 79%). LC-MS B: t_(R)=1.06 min; [M+H]⁺=326.19.

A.1.102.3. 5-Bromo-7-fluoro-6-methoxybenzo[b]thiophene

A mixture of crude5-bromo-7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylic acid (4.082 g,12.70 mmol) and copper(I) oxide (1.915 g, 13.40 mmol) in DMF (40 mL) isheated to 140° C., under nitrogen, overnight. The RM is allowed to coolto RT and is filtered over celite to remove copper salts that are washedwith Et₂O. Water and Et₂O are added to the filtrate and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=3/1) affords5-bromo-7-fluoro-6-methoxybenzo[b]thiophene as a yellow solid (1.413 g,42%). LC-MS B: t_(R)=1.03 min; no ionization.

A.1.102.4. 5-Bromo-7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylic acid

A mixture of methyl5-bromo-7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylate (4.066 g,12.70 mmol) in THE (60 mL), MeOH (8 mL) and water (20 mL) is treatedportionwise with lithium hydroxide (0.915 g, 38.20 mmol). The resultingmixture is stirred at RT for 1 h. The cooled (0° C.) RM is thenacidified by addition of 2 M aq. HCl and the organic solvents areremoved under reduced pressure. The obtained suspension is filtered andthe separated solid is washed with water and dried under high vacuum togive crude 5-bromo-7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylic acidas an off-white solid (4.082 g, quantitative). LC-MS B: t_(R)=0.92 min;no ionization.

A.1.102.5. Methyl5-bromo-7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylate

To a cooled (0° C.) suspension of5-bromo-2,3-difluoro-4-methoxybenzaldehyde (3.635 g, 13.70 mmol) andpotassium carbonate (2.904 g, 20.60 mmol) in DMF (30 mL) is addeddropwise methyl 2-mercaptoacetate (1.55 mL, 16.50 mmol) and the mixtureis stirred at RT for 1 h, and then heated to 60° C. for 1.5 h. The RM isallowed to cool to RT, water is added and the resulting suspension isstirred at RT for 15 min. After filtration, the obtained solid is washedwith water and dried under high vacuum to give methyl5-bromo-7-fluoro-6-methoxybenzo[b]thiophene-2-carboxylate as a colorlesssolid (4.066 g, 93%). LC-MS B: t_(R)=1.08 min; no ionization.

A.1.102.6. 5-Bromo-2,3-difluoro-4-methoxybenzaldehyde

To a solution of 5-bromo-2,3-difluoro-4-hydroxybenzaldehyde (4.700 g,19.10 mmol) in anh. DMF (50 mL) at RT are added cesium carbonate (7.475g, 22.90 mmol) and iodomethane (2.40 mL, 38.20 mmol) and the resultingmixture is stirred at RT, under nitrogen, overnight. Water and Et₂O areadded and the layers are separated. The aqueous layer is extracted twicewith Et₂O and the combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords5-bromo-2,3-difluoro-4-methoxybenzaldehyde as an off-white solid (3.635g, 76%). LC-MS B: t_(R)=0.92 min; no ionization.

A.1.102.7. 5-Bromo-2,3-difluoro-4-hydroxybenzaldehyde

A cooled (0° C.) solution of 2,3-difluoro-4-hydroxybenzaldehyde (4.600g, 27.90 mmol) and diisopropylamine (0.391 mL, 2.79 mmol) in anh. DCM(20 mL) is treated dropwise with a solution of N-bromosuccinimide (5.220g, 29.30 mmol) in anh. DCM (130 mL). The resulting mixture is furtherstirred at 0° C., under nitrogen, for 1 h. Water is added and the layersare separated. The aqueous layer is extracted twice with DCM and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords5-bromo-2,3-difluoro-4-hydroxybenzaldehyde as a beige solid (4.575 g,69%). LC-MS B: t_(R)=0.77 min: no ionization.

A.1.103.6-Chloro-N-(2-(3-chlorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

To a solution of 2-(3-chlorobenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride (0.537 g, 1.94 mmol) in 2-propanol (15 mL) at RT are addedTEA (0.947 mL, 6.80 mmol) and 4,6-dichloropyrimidine (0.347 g, 2.33mmol) and the mixture is refluxed (90° C.), under nitrogen, for 2 h. TheRM is allowed to cool to RT, DCM and water are added and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are then washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords6-chloro-N-(2-(3-chlorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine asa light yellow solid (0.574 g, 91%). LC-MS B: t_(R)=1.04 min;[M+H]⁺=324.03.

A.1.103.1. 2-(3-Chlorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

To a solution of tert-butyl(2-(3-chlorobenzo[b]thiophen-5-yl)ethyl)carbamate (943 mg, 2.57 mmol) inDCM (15 mL) is added 4 M HCl in dioxane (6.5 mL, 26.0 mmol) and themixture is stirred at RT for 2 h. The RM is then cooled in an ice bathfor 15 min and the obtained solid is filtered off and further driedunder high vacuum to afford2-(3-chlorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride as a lightorange solid (537 mg, 84%). LC-MS B: t_(R)=0.63 min; [M+H]⁺=212.16.

A.1.103.2. Tert-butyl(2-(3-chlorobenzo[b]thiophen-5-yl)ethyl)carbamate

A mixture of 5-bromo-3-chlorobenzo[b]thiophene (1.275 g, 3.78 mmol),potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.957 g,3.81 mmol) and cesium carbonate (3.690 g, 11.30 mmol) in toluene (24 mL)and water (12 mL) is degassed three times with nitrogen. Palladium(II)acetate (42.4 mg, 0.18 mmol) and RuPhos (185 mg, 0.37 mmol) are thenadded and the mixture is heated to 95° C., under nitrogen, overnight.The RM is allowed to cool to RT, water is added and the mixture isextracted twice with EtOAc. The combined organic layers are then washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=7/3)affords tert-butyl (2-(3-chlorobenzo[b]thiophen-5-yl)ethyl)carbamate asa light yellow solid (0.943 g, 80%). LC-MS B: t_(R)=1.06 min; noionization.

A.1.103.3. 5-Bromo-3-chlorobenzo[b]thiophene

A mixture of 5-bromo-3-chlorobenzo[b]thiophene-2-carboxylic acid (1.529g, 3.89 mmol) and copper(I) oxide (0.278 g, 1.95 mmol) in DMF (35 mL) isheated to 140° C., under nitrogen, overnight. The RM is allowed to coolto RT and is filtered over celite to remove copper salts that are washedwith Et₂O. Water and Et₂O are added to the filtrate and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=4/1) affords5-bromo-3-chlorobenzo[b]thiophene as a colorless solid (1.275 g, 96%).LC-MS B: t_(R)=1.06 min; no ionization.

A.1.103.4. 5-Bromo-3-chlorobenzo[b]thiophene-2-carboxylic acid

A solution of methyl 5-bromo-3-chlorobenzo[b]thiophene-2-carboxylate(1.604 g, 4.56 mmol) in THE (44 mL), MeOH (5 mL) and water (15 mL) istreated portionwise with lithium hydroxide (0.334 g, 13.70 mmol) and themixture is stirred at RT for 1 h. The cooled (0° C.) RM is thenacidified by addition of 2 M aq. HCl and the organic solvents areremoved under reduced pressure. The resulting suspension is filtered andthe obtained solid is washed with water and dried under high vacuum togive crude 5-bromo-3-chlorobenzo[b]thiophene-2-carboxylic acid as alight yellow solid (1.529 g, 82%). LC-MS B: t_(R)=0.93 min; noionization.

A.1.103.5. Methyl 5-bromo-3-chlorobenzo[b]thiophene-2-carboxylate

To a solution of methyl 3-amino-5-bromobenzo[b]thiophene-2-carboxylate(4.000 g, 13.30 mmol) in anh. MeCN (70 mL) is added copper(II) chloride(1.841 g, 13.30 mmol) and the mixture is heated to 45° C., undernitrogen. A solution of tert-butyl nitrite (1.74 mL, 14.60 mmol) in anh.MeCN (2 mL) is then added dropwise and the resulting mixture is heatedat 45° C., under nitrogen, for 1 h. The RM is then allowed to cool to RTand is concentrated to dryness under reduced pressure. DCM is added,solids are removed by filtration and the filtrate is concentrated todryness under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/1) affords methyl5-bromo-3-chlorobenzo[b]thiophene-2-carboxylate as a yellow solid (1.604g, 40%). LC-MS B: t_(R)=1.09 min; no ionization.

A.1.104.6-Chloro-N-(2-(4-fluorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

To a solution of 2-(4-fluorobenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride (1.109 g, 4.79 mmol) in 2-propanol (24 mL) at RT are addedTEA (1.67 mL, 12.00 mmol) and 4,6-dichloropyrimidine (0.856 g, 5.74mmol) and the mixture is refluxed (90° C.), under nitrogen, for 1 h. TheRM is then allowed to cool to RT, DCM and water are added and the layersare separated. The aq. layer is extracted twice with DCM and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to EtOAc) affords6-chloro-N-(2-(4-fluorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine asa colorless solid (1.269 g, 86%). LC-MS B: t_(R)=1.00 min;[M+H]⁺=308.13.

A.1.104.1. 2-(4-Fluorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride

To a solution of tert-butyl(2-(4-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate (1.620 g, 5.48 mmol)in DCM (27 mL) is added 4 M HCl in dioxane (8.2 mL, 32.8 mmol) and themixture is stirred at RT overnight. The RM is then filtered to afford2-(4-fluorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride as acolorless solid that was further dried under high vacuum (1.109 g, 87%).LC-MS B: t_(R)=0.57 min; [M+H]⁺=196.07.

A.1.104.2. Tert-butyl (2-(4-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate

A mixture of 4-fluorobenzo[b]thiophen-5-yl trifluoromethanesulfonate(2.160 g, 7.19 mmol), potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (1.987 g, 7.91mmol) and cesium carbonate (7.032 g, 21.60 mmol) in toluene (34 mL) andwater (8.5 mL) is degassed three times with nitrogen. Palladium(II)acetate (80.8 mg, 0.36 mmol) and RuPhos (353 mg, 0.71 mmol) are thenadded and the mixture is heated to 95° C., under nitrogen, overnight.The RM is allowed to cool to RT, water is added and the mixture isextracted twice with EtOAc. The combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=1/1) affordstert-butyl (2-(4-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate as a yellowoil (1.620 g, 76%). LC-MS B: t_(R)=1.02 min; no ionization.

A.1.104.3. 4-Fluorobenzo[b]thiophen-5-yl trifluoromethanesulfonate

A solution of 4-fluorobenzo[b]thiophen-5-ol (1.230 g, 7.31 mmol) and TEA(2.65 mL, 19.00 mmol) in anh. DCM (38 mL) is treated portionwise at RTwith1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(3.167 g, 8.78 mmol) and the mixture is stirred at RT, under nitrogen,overnight. The RM is then concentrated to dryness under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=1/1) affords4-fluorobenzo[b]thiophen-5-yl trifluoromethanesulfonate as a yellowsolid (2.160 g, 98%). LC-MS B: t_(R)=1.10 min; no ionization.

A.1.104.4. 4-Fluorobenzo[b]thiophen-5-ol

A mixture of 4-fluoro-5-(methoxymethoxy)benzo[b]thiophene (2.050 g, 9.84mmol) in MeOH (22 mL) and DCM (22 mL) is treated with 12 M aq. HCl (1.64mL; 19.68 mmol) and the resulting suspension is stirred at RT overnight.Water and DCM are added and the layers are separated. The aqueous layeris extracted twice with DCM and the combined organic layers are washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=3/2)affords 4-fluorobenzo[b]thiophen-5-ol as an orange oil (1.230 g, 74%).LC-MS B: t_(R)=0.77 min; no ionization.

A.1.104.5. 4-Fluoro-5-(methoxymethoxy)benzo[b]thiophene

To a cooled (−78° C.) solution of4-bromo-5-(methoxymethoxy)benzo[b]thiophene (2.730 g, 9.99 mmol;preparation described in A.1.95.6.) in anh. Et₂O (100 mL) is addeddropwise a solution of BuLi (1.6 M in hexanes, 6.20 mL, 9.92 mmol) andthe mixture is further stirred at −78° C., under nitrogen, for 10 min. Asolution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (3.249 g, 9.99mmol) in anh. THE (100 mL) is added dropwise to the previous mixture andstirring is continued at −78° C., under nitrogen, for 25 min. The cooled(0° C.) RM is then treated dropwise with water and is allowed to warm-upto RT. EtOAc is added and the layers are separated. The aqueous layer isextracted twice with EtOAc and the combined organic layers are washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=1/1)affords 4-fluoro-5-(methoxymethoxy)benzo[b]thiophene as a yellow oil(1.906 g, 90%). LC-MS B: t_(R)=0.93 min; no ionization.

A.1.105.6-Chloro-N-(2-(7-methylbenzo[b]thiophen-6-yl)ethyl)pyrimidin-4-amine

To a solution of 2-(7-methylbenzo[b]thiophen-6-yl)ethan-1-aminehydrochloride (0.448 g, 1.97 mmol) in 2-propanol (10 mL) at RT are addedTEA (0.685 mL, 4.92 mmol) and 4,6-dichloropyrimidine (0.352 g, 2.36mmol) and the resulting mixture is refluxed (90° C.), under nitrogen,for 4 h. The RM is allowed to cool to RT, DCM and water are added andthe layers are separated. The aq. layer is extracted twice with DCM andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to EtOAc) affords6-chloro-N-(2-(7-methylbenzo[b]thiophen-6-yl)ethyl)pyrimidin-4-amine asa colorless solid (0.302 g, 51%). LC-MS B: t_(R)=1.02 min;[M+H]⁺=304.21.

A.1.105.1. 2-(7-Methylbenzo[b]thiophen-6-yl)ethan-1-amine hydrochloride

To a solution of tert-butyl(2-(7-methylbenzo[b]thiophen-6-yl)ethyl)carbamate (0.362 g, 1.24 mmol)in DCM (12 mL) is added 4 M HCl in dioxane (1.86 mL, 7.44 mmol) and themixture is stirred at RT for 2 h. The RM is then concentrated underreduced pressure affording2-(7-methylbenzo[b]thiophen-6-yl)ethan-1-amine hydrochloride as acolorless solid that is further dried under high vacuum (0.254 g, 90%).LC-MS B: t_(R)=0.59 min; [M+H]⁺=192.19.

A.1.105.2. Tert-butyl(2-(7-methylbenzo[b]thiophen-6-yl)ethyl)carbamate

A mixture of 6-bromo-7-methylbenzo[b]thiophene (0.338 g, 1.49 mmol),potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.411 g,1.64 mmol) and cesium carbonate (1.456 g, 4.47 mmol) in toluene (8 mL)and water (2 mL) is degassed three times with nitrogen. Palladium(II)acetate (16.7 mg, 0.074 mmol) and RuPhos (73.2 mg, 0.14 mmol) are thenadded and the mixture is heated to 95° C., under nitrogen, overnight.The RM is allowed to cool to RT, water is added and the mixture isextracted twice with EtOAc. The combined organic layers are then washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=1/1)affords tert-butyl (2-(7-methylbenzo[b]thiophen-6-yl)ethyl)carbamate asa yellow oil (0.362 g, 83%). LC-MS B: t_(R)=1.05 min; no ionization.

A.1.105.3. 6-Bromo-7-methylbenzo[b]thiophene

A mixture of 6-bromo-7-methylbenzo[b]thiophene-2-carboxylic acid (0.492g, 1.81 mmol) and copper(I) oxide (64.9 mg, 0.45 mmol) in DMF (9 mL) isheated to 140° C., under nitrogen, overnight. The RM is allowed to coolto RT and is filtered over celite to remove copper salts that are washedwith Et₂O. Water and Et₂O are added to the filtrate and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=9/1) affords6-bromo-7-methylbenzo[b]thiophene as a yellow oil (0.338 g, 82%). LC-MSB: t_(R)=1.04 min; no ionization.

A.1.105.4. 6-Bromo-7-methylbenzo[b]thiophene-2-carboxylic acid

A mixture of methyl 6-bromo-7-methylbenzo[b]thiophene-2-carboxylate(0.538 g, 1.83 mmol) in THE (15 mL), MeOH (1.5 mL) and water (5 mL) istreated portionwise with lithium hydroxide (0.131 g, 5.49 mmol) and theresulting mixture is stirred at RT for 45 min. The cooled (0° C.) RM isthen acidified by addition of 2 M aq. HCl and the organic solvents areremoved under reduced pressure. The resulting suspension is filtered andthe obtained solid is washed with water and dried under high vacuum togive 6-bromo-7-methylbenzo[b]thiophene-2-carboxylic acid as a colorlesssolid (0.492 g, 99%). LC-MS B: t_(R)=0.92 min; no ionization.

A.1.105.5. Methyl 6-bromo-7-methylbenzo[b]thiophene-2-carboxylate

To a cooled (0° C.) mixture of 4-bromo-2-fluoro-3-methylbenzaldehyde(1.638 g, 7.40 mmol) and potassium carbonate (1.565 g, 11.10 mmol) inDMF (20 mL) is added dropwise methyl 2-mercaptoacetate (0.835 mL, 8.88mmol) and the resulting mixture is stirred at RT, under nitrogen, for 1h. Water and EtOAc are added and the layers are separated. The aqueouslayer is extracted twice with EtOAc and the combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=4/1) affords methyl6-bromo-7-methylbenzo[b]thiophene-2-carboxylate as a colorless solid(0.538 g, 26%). LC-MS B: t_(R)=1.08 min; no ionization.

A.1.105.6. 4-Bromo-2-fluoro-3-methylbenzaldehyde

To a cooled (0° C.) suspension of pyridinium chlorochromate (2.509 g,11.60 mmol) in anh. DCM (30 mL) is added a solution of(4-bromo-2-fluoro-3-methylphenyl)methanol (1.700 g, 7.76 mmol) in anh.DCM (25 mL) and the resulting mixture is stirred at 0° C., undernitrogen, for 15 min, and then at RT for 4 h. The RM is filtered overcelite washing with DCM, and the filtrate is concentrated under reducedpressure. Purification by FC (DCM) affords4-bromo-2-fluoro-3-methylbenzaldehyde as a colorless solid (1.638 g,97%). LC-MS B: t_(R)=0.92 min; no ionization.

A.1.105.7. (4-Bromo-2-fluoro-3-methylphenyl)methanol

To a cooled (−78° C.) solution of methyl4-bromo-2-fluoro-3-methylbenzoate (2.000 g, 7.85 mmol) in anh. toluene(55 mL) is added dropwise a solution of diisobutylaluminum hydride (1 Min toluene, 23.6 mL, 23.6 mmol). The resulting mixture is furtherstirred at −78° C., under nitrogen, for 45 min, and then at 0° C. for 30min. The cooled RM is treated successively with water (22 mL) and with2.8 N aq. NaOH (0.5 mL), and stirring is continued at RT for 1 h. EtOAcand water are added, the layers are separated and the aqueous layer isextracted twice with EtOAc. The combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure affording(4-bromo-2-fluoro-3-methylphenyl)methanol as a colorless solid that isfurther dried under high vacuum (1.700 g, 99%). LC-MS B: t_(R)=0.81 min;no ionization.

A.1.106.6-Chloro-N-(2-(7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

To a solution of2-(7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride (1.000 g, 3.55 mmol) in 2-propanol (20 mL) at RT are addedTEA (1.24 mL, 8.88 mmol) and 4,6-dichloropyrimidine (0.635 g, 4.26 mmol)and the resulting mixture is refluxed (95° C.), under nitrogen, for 2.5h. The RM is allowed to cool to RT, DCM and water are added and thelayers are separated. The aq. layer is extracted twice with DCM and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to EtOAc) affords6-chloro-N-(2-(7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amineas a colorless solid (1.290 g, quantitative). LC-MS B: t_(R)=0.95 min;[M+H]⁺=358.07.

A.1.106.1.2-(7-(Difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride

To a solution of tert-butyl(2-(7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate(1.970 g, 5.70 mmol) in DCM (25 mL) is added 4 M HCl in dioxane (8.55mL, 34.20 mmol) and the mixture is stirred at RT for 1.5 h. The RM isconcentrated under reduced pressure affording2-(7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride as a colorless solid that is further dried under highvacuum (1.480 g, 92%). LC-MS B: t_(R)=0.54 min; [M+H]⁺=246.10.

A.1.106.2. Tert-butyl(2-(7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

A mixture of 6-bromo-7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxine(1.900 g, 6.76 mmol), potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (1.867 g, 7.44mmol) and cesium carbonate (6.608 g, 20.30 mmol) in toluene (45 mL) andwater (15 mL) is degassed three times with nitrogen. Palladium(II)acetate (76 mg, 0.33 mmol) and RuPhos (332 mg, 0.67 mmol) are then addedand the mixture is heated to 95° C., under nitrogen, overnight. The RMis allowed to cool to RT, water is added and the mixture is extractedtwice with EtOAc. The combined organic layers are washed with brine,dried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affordstert-butyl(2-(7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamateas a pale yellow solid (1.970 g, 84%). LC-MS B: t_(R)=0.99 min; noionization.

A.1.106.3. 6-Bromo-7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxine

To a cooled (0° C.) solution of7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (1.850 g, 8.01 mmol) in MeCN(45 mL) and water (45 mL) is added potassium hydroxide (8.986 g, 160.00mmol), and the mixture is stirred at RT for 30 min. The resultingmixture is cooled to −30° C., treated with diethyl(bromodifluoromethyl)phosphonate (2.9 mL, 16.00 mmol) in one portion andstirred at RT for 75 min. The RM is diluted with Et₂O, the layers areseparated and the aqueous layer is extracted twice with Et₂O. Thecombined organic layers are successively washed with 1 M aq. NaOH, waterand brine and are then dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/7) affords6-bromo-7-(difluoromethoxy)-2,3-dihydrobenzo[b][1,4]dioxine as acolorless solid (1.900 g, 84%). LC-MS B: t_(R)=0.96 min; no ionization.

A.1.106.4. 7-Bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-ol

To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (5.000 g, 31.20mmol) in anh. DMF (50 mL) at RT is added portionwise N-bromosuccinimide(5.557 g, 31.22 mmol) and the mixture is stirred at RT, under nitrogen,for 2 h. A second addition of N-bromosuccinimide (1.111 g, 6.24 mmol) isperformed and the resulting mixture is further stirred at RT, undernitrogen, for 30 min. The RM is treated with water and is extractedthree times with Et₂O/EtOAc. The combined organic layers are washed withwater and brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=3/2)affords 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-ol as a red oil (4.120g, 57%). LC-MS B: t_(R)=0.75 min; no ionization.

A.1.107.6-Chloro-N-(2-(7-((triisopropylsilyl)ethynyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

To a solution of2-(7-((triisopropylsilyl)ethynyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine(0.770 g, 2.14 mmol) in 2-propanol (21 mL) at RT are added TEA (0.745mL, 5.35 mmol) and 4,6-dichloropyrimidine (0.383 g, 2.57 mmol) and theresulting mixture is refluxed (90° C.), under nitrogen, for 2 h. The RMis allowed to cool to RT, DCM and water are added and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to EtOAc) affords6-chloro-N-(2-(7-((triisopropylsilyl)ethynyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amineas a pale yellow oil (0.723 g, 72%). LC-MS B: t_(R)=1.29 min;[M+H]⁺=472.21.

A.1.107.1.2-(7-((Triisopropylsilyl)ethynyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

To a solution of tert-butyl(2-(7-((triisopropylsilyl)ethynyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate(0.870 g, 1.89 mmol) in MeOH (9.5 mL) is added chlorotrimethylsilane(1.21 mL, 9.46 mmol) and the mixture is stirred at RT for 4.5 h. The RMis treated carefully with aq. sat. NaHCO₃ and the resulting mixture isextracted three times with DCM. The combined organic layers are driedover anh. MgSO₄, filtered and concentrated under reduced pressure toafford2-(7-((triisopropylsilyl)ethynyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amineas an orange oil (0.679 g, 99%). LC-MS B: t_(R)=0.92 min; [M+H]⁺=360.20.

A.1.107.2. Tert-butyl(2-(7-((triisopropylsilyl)ethynyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

To a solution of tert-butyl(2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate (1.340 g,3.31 mmol) in TEA (22 mL) are added successively copper(I) iodide (88mg, 0.46 mmol) and PdCl₂(PPh₃)₂ (117 mg, 0.16 mmol), and the resultingmixture is degassed with nitrogen. (Triisopropylsilyl)acetylene (1.48mL, 6.61 mmol) is then added and the mixture is heated to 50° C., undernitrogen, for 2 h. The RM is filtered over celite and the filtrate isconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=4/1) affords tert-butyl(2-(7-((triisopropylsilyl)ethynyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamateas a yellow oil (1.060 g, 70%). LC-MS B: t_(R)=1.30 min; [M+H]⁺=460.28.

A.1.107.3. Tert-butyl(2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

A solution of tert-butyl(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate (0.950 g, 3.40mmol) in MeCN (9 mL) and water (9 mL) is treated with N-iodosuccinimide(3.222 g, 13.60 mmol) and the mixture is stirred at RT for 2 h. The RMis treated with aq. sat. sodium thiosulfate and extracted three timeswith EtOAc. The combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=3/7) affordstert-butyl(2-(7-iodo-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate as anoff-white solid (1.340 g, quantitative). LC-MS B: t_(R)=1.01 min;[M+H]⁺=406.05.

A.1.107.4. Tert-butyl(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

A mixture of 6-bromo-2,3-dihydrobenzo[b][1,4]dioxine (1.081 g, 4.87mmol), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate(1.417 g, 5.36 mmol) and cesium carbonate (4.764 g, 14.60 mmol) intoluene (33 mL) and water (11 mL) is degassed three times with nitrogen.Palladium(II) acetate (54.8 mg, 0.244 mmol) and RuPhos (239 mg, 0.48mmol) are added and the mixture is heated to 90° C., under nitrogen, for4 h. The RM is allowed to cool to RT, water is added and the mixture isextracted three times with EtOAc. The combined organic layers are washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=1/1)affords tert-butyl(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate as a pale yellowsolid (1.230 g, 90%). LC-MS B: t_(R)=0.91 min; no ionization.

A.1.108.6-Chloro-N-(2-(7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

To a solution of2-(7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride (0.300 g, 1.16 mmol) in 2-propanol (20 mL) at RT are addedTEA (0.40 mL, 2.89 mmol) and 4,6-dichloropyrimidine (0.206 g, 1.39 mmol)and the mixture is refluxed (95° C.), under nitrogen, for 2 h. The RM isthen allowed to cool to RT, DCM and water are added, and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to EtOAc) affords6-chloro-N-(2-(7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amineas a colorless solid (0.343 g, 88%). LC-MS B: t_(R)=0.98 min;[M+H]⁺=336.14.

A.1.108.1.2-(7-Methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride

To a solution of tert-butyl(2-(7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate(1.520 g, 4.70 mmol) in DCM (25 mL) is added 4 M HCl in dioxane (7.0 mL,28.0 mmol) and the mixture is stirred at RT overnight. The RM isconcentrated under reduced pressure and the obtained solid is trituratedin DCM. The solid is filtered, washed with DCM and dried under highvacuum to afford2-(7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride as a colorless solid (0.625 g, 51%). LC-MS B: t_(R)=0.57min; [M+H]⁺=224.26.

A.1.108.2. Tert-butyl(2-(7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

A mixture of 7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate (1.600 g, 4.87 mmol), potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (1.417 g, 5.36mmol) and cesium carbonate (4.764 g, 14.60 mmol) in toluene (33 mL) andwater (11 mL) is degassed three times with nitrogen. Palladium(II)acetate (54.8 mg, 0.24 mmol) and RuPhos (239 mg, 0.48 mmol) are addedand the mixture is heated to 95° C., under nitrogen, overnight. The RMis allowed to cool to RT, water is added and the mixture is extractedthree times with EtOAc. The combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=1/1) affordstert-butyl(2-(7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamateas a colorless solid (1.520 g, 96%). LC-MS B: t_(R)=1.01 min;[M+H]⁺=324.22.

A.1.108.3. 7-Methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate

A solution of 7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ol(1.140 g, 5.81 mmol) and TEA (2.11 mL, 15.10 mmol) in anh. DCM (54 mL)is treated portionwise at RT with1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(2.516 g, 6.97 mmol) and the mixture is stirred at RT, under nitrogen,overnight. The RM is concentrated to dryness under reduced pressure andsubsequent purification by FC (from heptane to heptane/EtOAc=1/1)affords 7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate as a colorless oil (1.600 g, 84%). LC-MS B:t_(R)=1.07 min; no ionization.

A.1.108.4. 7-Methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ol

A mixture of7-methoxy-6-(methoxymethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]dioxine(1.423 g, 5.92 mmol) in MeOH (13 mL) and DCM (13 mL) is treated with 12M aq. HCl (1.0 mL; 12.0 mmol) and the resulting suspension is stirred atRT overnight. Water and DCM are added and the layers are separated. Theaqueous layer is extracted twice with DCM and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toEtOAc) affords 7-methoxy-5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-ol asa colorless solid (1.140 g, 98%). LC-MS B: t_(R)=0.74 min; noionization.

A.1.108.5.7-Methoxy-6-(methoxymethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]dioxine

A mixture of5-bromo-7-methoxy-6-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine(0.909 g, 2.98 mmol) and Cs₂CO₃ (2.941 g, 8.94 mmol) in DMF (13 mL) isdegassed with nitrogen. Pd(PPhs)₄ (344 mg, 0.29 mmol) and2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (393 mg, 3.10 mmol) areadded and the mixture is degassed again with nitrogen. The resultingmixture is then heated to 90° C., under nitrogen, overnight. The RM isallowed to cool to RT and diluted with Et₂O and water. The layers areseparated and the aqueous layer is extracted twice with Et₂O. Thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords7-methoxy-6-(methoxymethoxy)-5-methyl-2,3-dihydrobenzo[b][1,4]dioxine asa colorless oil (0.599 g, 84%). LC-MS B: t_(R)=0.84 min; [M+H]⁺=241.16.

A.1.108.6.5-Bromo-7-methoxy-6-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine

A cooled (0° C.) solution of5-bromo-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (2.516 g, 9.64mmol) in anh. DMF (24 mL) is treated portionwise with sodium hydride(60% dispersion in mineral oil, 501 mg, 12.50 mmol) and the mixture isstirred at RT, under nitrogen, for 15 min. The cooled (0° C.) mixture istreated with chloromethyl methyl ether (1.46 mL, 19.30 mmol) and is thenstirred at RT, under nitrogen, overnight. Water and Et₂O are added andthe layers are separated. The organic layer is washed twice with water,dried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords5-bromo-7-methoxy-6-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine asa colorless oil (2.360 g, 80%). LC-MS B: t_(R)=0.87 min; no ionization.

A.1.108.7. 5-Bromo-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol

A cooled (0° C.) solution of7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (2.790 g, 15.30 mmol) inanh. DCM (20 mL) is treated with a solution of N-bromosuccinimide (2.998g, 16.80 mmol) in anh. DCM (80 mL), and the mixture is stirred at 0° C.,under nitrogen, for 5 min. Water is added and the layers are separated.The aqueous layer is extracted twice with DCM and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords5-bromo-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol as a pale orangesolid (2.353 g, 59%). LC-MS B: t_(R)=0.75 min; no ionization.

A.1.108.8. 7-Methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol

To a cooled (0° C.) solution of7-methoxy-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (5.000 g, 25.70mmol) in anh. DCM (100 mL) is added 3-chloroperbenzoic acid (11.541 g,51.50 mmol) and the resulting mixture is stirred at RT, under nitrogen,overnight. The RM is filtered over celite washing with DCM, and thefiltrate is concentrated to dryness under reduced pressure. MeOH and 4Naq. NaOH (56 mL) are added, and the resulting mixture is stirred at RTfor 1.5 h. MeOH is removed under reduced pressure and the residue isdiluted with aq. sat. NH₄Cl and extracted three times with EtOAc. Thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to EtOAc) affords7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol as a yellow oil (3.030 g,65%). LC-MS B: t_(R)=0.61 min; no ionization.

A.1.109.6-Chloro-N-(2-(5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

To a solution of2-(5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride (0.120 g, 0.44 mmol) in 2-propanol (10 mL) at RT are addedTEA (0.158 mL, 1.14 mmol) and 4,6-dichloropyrimidine (81.4 mg, 0.54mmol) and the mixture is refluxed (90° C.), under nitrogen, for 3 h. TheRM is allowed to cool to RT, DCM and water are added, and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to EtOAc) affords6-chloro-N-(2-(5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amineas a colorless solid (0.124 g, 81%). LC-MS B: t_(R)=0.94 min;[M+H]⁺=340.13.

A.1.109.1.2-(5-Fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride

To a solution of tert-butyl(2-(5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate(0.145 g, 0.44 mmol) in DCM (10 mL) is added 4 M HCl in dioxane (0.665mL, 2.66 mmol) and the mixture is stirred at RT overnight. The RM isconcentrated to dryness under reduced pressure and the obtained solid isdried under high vacuum to afford2-(5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride as a colorless solid (0.120 g, quantitative). LC-MS B:t_(R)=0.54 min; [M+H]⁺=228.23.

A.1.109.2. Tert-butyl(2-(5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

A mixture of 5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate (0.173 g, 0.52 mmol), potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.152 g, 0.57mmol) and cesium carbonate (0.510 g, 1.56 mmol) in toluene (3.5 mL) andwater (1.2 mL) is degassed three times with nitrogen. Palladium(II)acetate (6 mg, 0.026 mmol) and RuPhos (25.6 mg, 0.052 mmol) are addedand the mixture is heated to 95° C., under nitrogen, overnight. The RMis allowed to cool to RT, water is added and the mixture is extractedthree times with EtOAc. The combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=1/1) affordstert-butyl(2-(5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamateas a pale yellow solid (0.145 g, 85%). LC-MS B: t_(R)=0.98 min; noionization.

A.1.109.3. 5-Fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate

A solution of 5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol(0.121 g, 0.60 mmol) and TEA (0.219 mL, 1.57 mmol) in anh. DCM (10 mL)is treated portionwise at RT with1,1,1-trifluoro-N-phenyl-N-((trifuoromethyl)sulfonyl)methanesulfonamide(0.262 g, 0.72 mmol) and the mixture is stirred at RT, under nitrogen,overnight. The RM is concentrated to dryness under reduced pressure andsubsequent purification by FC (from heptane to heptane/EtOAc=1/1)affords 5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate as a colorless oil (0.173 g, 86%). LC-MS B:t_(R)=1.03 min; no ionization.

A.1.109.4. 5-Fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol

A mixture of5-fluoro-7-methoxy-6-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine(0.257 g, 1.05 mmol) in MeOH (2.5 mL) and DCM (2.5 mL) is treated with12 M aq. HCl (0.176 mL; 2.11 mmol) and the resulting suspension isstirred at RT overnight. Water and DCM are added and the layers areseparated. The aqueous layer is extracted twice with DCM and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=3/2) affords5-fluoro-7-methoxy-2,3-dihydrobenzo[b][1,4]dioxin-6-ol as a colorlesssolid (0.121 g, 57%). LC-MS B: t_(R)=0.66 min; no ionization.

A.1.109.5.5-Fluoro-7-methoxy-6-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine

To a cooled (−78° C.) solution of5-bromo-7-methoxy-6-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine(0.498 g, 1.82 mmol) in anh. Et₂O (18 mL) is added dropwise a solutionof BuLi (1.6 M in hexanes, 1.14 mL, 1.82 mmol) and the mixture isfurther stirred at −78° C., under nitrogen, for 10 min. A solution ofN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.592 g, 1.82 mmol) inanh. THE (18 mL) is then added dropwise and the resulting mixture isstirred at −78° C. for 25 min. The RM is treated dropwise with water andis allowed to warm-up to RT. EtOAc is added and the layers areseparated. The aqueous layer is extracted twice with EtOAc and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords5-fluoro-7-methoxy-6-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine asa pale yellow oil (0.257 g, 58%). LC-MS B: t_(R)=0.84 min;[M+H]⁺=245.25.

A.1.110.6-Chloro-N-(2-(7-(trifluoromethyl)benzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

To a solution of2-(7-(trifluoromethyl)benzo[b]thiophen-5-yl)ethan-1-amine hydrochloride(0.965 g, 3.43 mmol) in 2-propanol (20 mL) at RT are added TEA (1.67 mL,12.00 mmol) and 4,6-dichloropyrimidine (0.612 g, 4.11 mmol) and themixture is refluxed (90° C.), under nitrogen, for 2 h. The RM is allowedto cool to RT, DCM and water are added and the layers are separated. Theaq. layer is extracted twice with DCM and the combined organic layersare washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords6-chloro-N-(2-(7-(trifluoromethyl)benzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amineas a colorless solid (1.019 g, 83%). LC-MS B: t_(R)=1.06 min;[M+H]⁺=358.07.

A.1.110.1. 2-(7-(Trifluoromethyl)benzo[b]thiophen-5-yl)ethan-1-aminehydrochloride

To a solution of tert-butyl(2-(7-(trifluoromethyl)benzo[b]thiophen-5-yl)ethyl)carbamate (1.686 g,4.86 mmol) in DCM (15 mL) is added 4 M HCl in dioxane (12.2 mL, 48.8mmol) and the mixture is stirred at RT for 2 h. The RM is then cooled inan ice bath for 15 min and the obtained solid is filtered off andfurther dried under high vacuum to afford2-(7-(trifluoromethyl)benzo[b]thiophen-5-yl)ethan-1-amine hydrochlorideas a colorless solid (0.965 g, 71%). LC-MS B: t_(R)=0.69 min;[M+H]⁺=246.20.

A.1.110.2. Tert-butyl(2-(7-(trifluoromethyl)benzo[b]thiophen-5-yl)ethyl)carbamate

A mixture of 5-bromo-7-(trifluoromethyl)benzo[b]thiophene (1.690 g, 5.51mmol), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate(1.601 g, 6.06 mmol) and cesium carbonate (5.383 g, 16.50 mmol) intoluene (24 mL) and water (12 mL) is degassed three times with nitrogen.Palladium(II) acetate (62 mg, 0.27 mmol) and RuPhos (0.271 g, 0.55 mmol)are then added and the mixture is heated to 95° C., under nitrogen,overnight. The RM is allowed to cool to RT, water is added and themixture is extracted twice with EtOAc. The combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords tert-butyl(2-(7-(trifluoromethyl)benzo[b]thiophen-5-yl)ethyl)carbamate as a lightyellow solid (1.686 g, 89%). LC-MS B: t_(R)=1.09 min; no ionization.

A.1.110.3. 5-Bromo-7-(trifluoromethyl)benzo[b]thiophene

A mixture of 5-bromo-7-(trifluoromethyl)benzo[b]thiophene-2-carboxylicacid (2.658 g, 8.12 mmol) and copper(I) oxide (1.162 g, 8.12 mmol) inDMF (30 mL) is heated to 140° C. under nitrogen, overnight. The RM isallowed to cool to RT and is filtered over celite to remove copper saltsthat are washed with Et₂O. Water and Et₂O are added to the filtrate andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=7/3) affords5-bromo-7-(trifluoromethyl)benzo[b]thiophene as a clear oil (1.690 g,74%). LC-MS B: t_(R)=1.09 min; no ionization.

A.1.110.4. 5-Bromo-7-(trifluoromethyl)benzo[b]thiophene-2-carboxylicacid

A mixture of methyl5-bromo-7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate (2.930 g,8.64 mmol) in THE (45 mL), MeOH (6 mL) and water (15 mL) is treatedportionwise with lithium hydroxide (0.621 g, 25.90 mmol). The resultingmixture is stirred at RT for 1 h. The cooled (0° C.) RM is thenacidified by addition of 2 M aq. HCl and the organic solvents areremoved under reduced pressure. The resulting suspension is filtered andthe obtained solid is washed with water and dried under high vacuum togive 5-bromo-7-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid as acolorless solid (2.658 g, 95%). LC-MS B: t_(R)=0.98 min; no ionization.

A.1.110.5. Methyl5-bromo-7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate

To a cooled (0° C.) mixture of5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (3.000 g, 10.80 mmol)and potassium carbonate (2.295 g, 16.30 mmol) in DMF (25 mL) is addeddropwise methyl 2-mercaptoacetate (1.23 mL, 13.00 mmol) and theresulting mixture is stirred at RT for 2 h, and then at 60° C. for 1.5h. The RM is treated with water and stirred at RT for 15 min. Theresulting suspension is filtered and the obtained solid is washed withwater and dried under high vacuum to give methyl5-bromo-7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate as anoff-white solid (2.930 g, 80%). LC-MS B: t_(R)=1.13 min; no ionization.

A.1.111.6-Chloro-N-(2-(3-chloro-7-fluorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amine

To a solution of 2-(3-chloro-7-fluorobenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride (0.548 g, 2.05 mmol) in 2-propanol (15 mL) at RT are addedTEA (1.00 mL, 7.18 mmol) and 4,6-dichloropyrimidine (0.367 g, 2.46 mmol)and the mixture is refluxed (90° C.), under nitrogen, for 2 h. The RM isallowed to cool to RT, DCM and water are added and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to heptane/EtOAc=1/1) affords6-chloro-N-(2-(3-chloro-7-fluorobenzo[b]thiophen-5-yl)ethyl)pyrimidin-4-amineas a colorless solid (0.649 g, 92%). LC-MS B: t_(R)=1.04 min;[M+H]⁺=341.99.

A.1.111.1. 2-(3-Chloro-7-fluorobenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride

To a solution of tert-butyl(2-(3-chloro-7-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate (0.690 g,2.08 mmol) in DCM (10 mL) is added 4 M HCl in dioxane (5.2 mL, 20.8mmol) and the mixture is stirred at RT overnight. The RM is concentratedunder reduced pressure to afford2-(3-chloro-7-fluorobenzo[b]thiophen-5-yl)ethan-1-amine hydrochloride asa colorless solid (0.548 g, 99%). LC-MS B: t_(R)=0.64 min;[M+H]⁺=230.13.

A.1.111.2. Tert-butyl(2-(3-chloro-7-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate

A mixture of 5-bromo-3-chloro-7-fluorobenzo[b]thiophene (1.928 g, 7.26mmol), potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate(2.111 g, 7.99 mmol) and cesium carbonate (7.097 g, 21.80 mmol) intoluene (45 mL) and water (15 mL) is degassed three times with nitrogen.Palladium(II) acetate (82 mg, 0.36 mmol) and RuPhos (0.357 g, 0.72 mmol)are then added and the mixture is heated to 95° C., under nitrogen,overnight. The RM is allowed to cool to RT, water is added and themixture is extracted three times with EtOAc. The combined organic layersare washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=9/1) affords tert-butyl(2-(3-chloro-7-fluorobenzo[b]thiophen-5-yl)ethyl)carbamate as a yellowsolid (0.690 g, 29%). LC-MS B: t_(R)=1.06 min; no ionization.

A.1.111.3. 5-Bromo-3-chloro-7-fluorobenzo[b]thiophene

A mixture of 5-bromo-3-chloro-7-fluorobenzo[b]thiophene-2-carboxylicacid (3.632 g, 11.70 mmol) and copper(I) oxide (0.839 g, 5.87 mmol) inDMF (70 mL) is heated to 140° C., under nitrogen, overnight. The RM isallowed to cool to RT and is filtered over celite to remove copper saltsthat are washed with Et₂O. Water and Et₂O are added to the filtrate andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=9/1) affords5-bromo-3-chloro-7-fluorobenzo[b]thiophene as a colorless solid (2.228g, 72%). LC-MS B: t_(R)=1.06 min; no ionization.

A.1.111.4. 5-Bromo-3-chloro-7-fluorobenzo[b]thiophene-2-carboxylic acid

A mixture of methyl5-bromo-3-chloro-7-fluorobenzo[b]thiophene-2-carboxylate (3.813 g, 11.80mmol) in THE (44 mL), MeOH (5 mL) and water (15 mL) is treatedportionwise with lithium hydroxide (0.864 g, 35.40 mmol). The resultingmixture is stirred at RT for 1 h. The cooled (0° C.) RM is thenacidified by addition of 2 M aq. HCl and the organic solvents areremoved under reduced pressure. The resulting suspension is filtered andthe obtained solid is washed with water and dried under high vacuum togive 5-bromo-3-chloro-7-fluorobenzo[b]thiophene-2-carboxylic acid as alight yellow solid (3.632 g, 99%). LC-MS B: t_(R)=0.93 min; noionization.

A.1.111.5. Methyl5-bromo-3-chloro-7-fluorobenzo[b]thiophene-2-carboxylate

To a solution of methyl3-amino-5-bromo-7-fluorobenzo[b]thiophene-2-carboxylate (5.291 g, 17.40mmol) in anh. MeCN (60 mL) is added copper(II) chloride (2.411 g, 17.40mmol) and the mixture is heated to 45° C., under nitrogen. A solution oftert-butyl nitrite (2.27 mL, 19.10 mmol) in anh. MeCN (15 mL) is thenadded dropwise and the resulting mixture is heated at 45° C. undernitrogen, for 1.5 h. The RM is allowed to cool to RT and is concentratedto dryness under reduced pressure. DCM is added, solids are removed byfiltration and the filtrate is concentrated to dryness under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=7/3) affordsmethyl 5-bromo-3-chloro-7-fluorobenzo[b]thiophene-2-carboxylate as alight yellow solid (3.671 g, 65%). LC-MS B: t_(R)=1.09 min; noionization.

A.1.111.6. Methyl3-amino-5-bromo-7-fluorobenzo[b]thiophene-2-carboxylate

To a cooled (0° C.) mixture of 5-bromo-2,3-difluorobenzonitrile (4.010g, 17.70 mmol) and potassium carbonate (4.930 g, 35.30 mmol) in DMF (40mL) is added dropwise a solution of methyl 2-mercaptoacetate (1.66 mL,17.70 mmol) in DMF (10 mL) and the resulting mixture is stirred at 0° C.for 1 h. The RM is treated with water and stirred at RT for 15 min. Theresulting suspension is filtered and the obtained solid is washed withwater and dried under high vacuum to give methyl3-amino-5-bromo-7-fluorobenzo[b]thiophene-2-carboxylate as an off-whitesolid (5.489 g, quantitative). LC-MS B: t_(R)=1.04 min; [M+H]⁺=304.01.

A.1.112.6-Chloro-N-(2-(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

To a solution of2-(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine (1.774 g,7.17 mmol) in 2-propanol (25 mL) at RT are added TEA (1.57 mL, 11.20mmol) and 4,6-dichloropyrimidine (0.574 g, 3.86 mmol) and the mixture isrefluxed (90° C.), under nitrogen, for 1.5 h. The RM is allowed to coolto RT, DCM and water are added and the layers are separated. The aq.layer is extracted twice with DCM and the combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords6-chloro-N-(2-(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amineas a yellow solid (1.080 g, 49%). LC-MS B: t_(R)=0.92 min;[M+H]⁺=305.94.

A.1.112.1. 2-(5-Methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine

To a solution of 5-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde(1.387 g, 7.72 mmol) in nitromethane (15 mL) are added successively 4Amolecular sieves (180 mg), butylamine (0.091 mL, 0.91 mmol) and aceticacid (0.090 mL, 1.58 mmol) and the resulting mixture is heated to 90°C., under nitrogen, for 30 min. The RM is filtered and the filtrate isconcentrated under reduced pressure affording crude(E)-5-methyl-6-(2-nitrovinyl)-2,3-dihydrobenzo[b][1,4]dioxine as anorange solid (1.978 g, quantitative). LC-MS B: t_(R)=0.95 min; noionisation

To a cooled (0° C.) solution of crude(E)-5-methyl-6-(2-nitrovinyl)-2,3-dihydrobenzo[b][1,4]dioxine (1.978 g,7.72 mmol) in anh. THE (15 mL) is added dropwise a solution of lithiumaluminum hydride (2 M in THF, 12.5 mL, 25.0 mmol) and the mixture isheated at reflux (70° C.), under nitrogen, for 15 min. The cooled (0°C.) RM is treated successively with water, 15% aq. NaOH, and water andis further stirred at 0° C. for 1 h. The resulting heterogeneous mixtureis filtered and the separated solids are washed with Et₂O. The layers ofthe filtrate are separated and the aqueous layer is extracted with Et₂O.The combined organic layers are dried over anh. MgSO₄, filtered andconcentrated under reduced pressure to afford crude2-(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine as anamber oil (1.774 g, quantitative). LC-MS B: t_(R)=0.51 min;[M+H]⁺=194.28.

A.1.112.2. 5-Methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde

To a cooled (0° C.) suspension of pyridinium chlorochromate (3.051 g,14.20 mmol) in DCM (30 mL) is added a solution of(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol (1.723 g, 9.44mmol) in DCM (25 mL). The resulting suspension is further stirred at 0°C., under nitrogen, for 15 min and then at RT for 1 h. The RM isfiltered over celite and the filtrate is concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=1/1) affords5-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde as an off-whitesolid (1.387 g, 83%). LC-MS B: t_(R)=0.81 min; [M+H]⁺=179.32.

A.1.112.3. (5-Methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol

To a cooled (−78° C.) solution of methyl5-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (2.054 g, 9.78mmol) in anh. toluene (55 mL) is added dropwise a solution ofdiisobutylaluminum hydride (1 M in toluene, 29.6 mL, 29.6 mmol). Themixture is further stirred at −78° C., under nitrogen, for 30 min and isthen allowed to warm-up to 0° C. Stirring at 0° C. is continued for 45min, and the cooled RM is treated successively with water (22 mL) andwith 2.8 N aq. NaOH (0.5 mL). The mixture is allowed to warm-up to RTand is further stirred for 1 h. The resulting mixture is filtered overcelite, EtOAc and water are added and the layers are separated. Theaqueous layer is extracted twice with EtOAc and the combined organiclayers are dried over anh. MgSO₄, filtered and concentrated underreduced pressure to afford(5-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methanol as a colorlessoil (1.723 g, 97%). LC-MS B: t_(R)=0.65 min; no ionization.

A.1.112.4. Methyl 5-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate

To a solution of 5-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylicacid (2.000 g, 9.78 mmol) in anh. DMF (20 mL) at RT are added cesiumcarbonate (6.376 g, 19.60 mmol) and iodomethane (1.23 mL, 19.60 mmol)and the mixture is stirred at RT for 1 h. Water and Et₂O are added andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords methyl5-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate as a colorlesssolid (2.054 g, quantitative). LC-MS B: t_(R)=0.89 min; [M+H]⁺=209.20.

A.1.113.6-Chloro-N-(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amine

To a solution of2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride (0.206 g, 0.88 mmol) in 2-propanol (10 mL) at RT are addedTEA (0.43 mL, 3.09 mmol) and 4,6-dichloropyrimidine (0.158 g, 1.06 mmol)and the mixture is refluxed (90° C.), under nitrogen, for 2 h. The RM isallowed to cool to RT, DCM and water are added, and the layers areseparated. The aq. layer is extracted twice with DCM and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to EtOAc) affords6-chloro-N-(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)pyrimidin-4-amineas a colorless solid (0.224 g, 82%). LC-MS B: t_(R)=0.90 min;[M+H]⁺=310.18.

A.1.113.1. 2-(7-Fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride

To a solution of tert-butyl(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate (0.321g, 1.08 mmol) in DCM (10 mL) is added 4 M HCl in dioxane (1.62 mL, 6.48mmol) and the mixture is stirred at RT overnight. The RM is concentratedto dryness under reduced pressure and the obtained solid is dried underhigh vacuum to afford2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-aminehydrochloride as a colorless solid (0.206 g, 82%). LC-MS B: t_(R)=0.48min; [M+H]⁺=198.20.

A.1.113.2. Tert-butyl(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate

A mixture of 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate (0.358 g, 1.18 mmol), potassium(2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (0.327 g, 1.30mmol) and cesium carbonate (1.157 g, 3.55 mmol) in toluene (9 mL) andwater (3 mL) is degassed three times with nitrogen. Palladium(II)acetate (13 mg, 0.059 mmol) and RuPhos (58 mg, 0.118 mmol) are added andthe mixture is heated to 95° C., under nitrogen, overnight. The RM isallowed to cool to RT, water is added and the mixture is extracted threetimes with EtOAc. The combined organic layers are washed with brine,dried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=3/7) affordstert-butyl(2-(7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)carbamate as apale yellow oil (0.321 g, 91%). LC-MS B: t_(R)=0.94 min; no ionization.

A.1.113.3. 7-Fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate

A solution of 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (0.242 g,1.42 mmol) and TEA (0.516 mL, 3.70 mmol) in anh. DCM (15 mL) is treatedportionwise at RT with1,1,1-trifluoro-N-phenyl-N-((trifuoromethyl)sulfonyl)methanesulfonamide(0.617 g, 1.71 mmol) and the mixture is stirred at RT, under nitrogen,overnight. The RM is concentrated to dryness under reduced pressure anda subsequent purification by FC (from heptane to heptane/EtOAc=7/3)affords 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yltrifluoromethanesulfonate as a colorless oil (0.357 g, 83%). LC-MS B:t_(R)=1.01 min; no ionization.

A.1.113.4. 7-Fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol

A mixture of 6-fluoro-7-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine(0.524 g, 2.45 mmol) in MeOH (5 mL) and DCM (5 mL) is treated with 12 Maq. HCl (0.407 mL; 4.88 mmol) and the resulting suspension is stirred atRT overnight. Water and DCM are added and the layers are separated. Theaqueous layer is extracted twice with DCM and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/2) affords 7-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-olas a colorless solid (0.325 g, 78%). LC-MS B: t_(R)=0.63 min: noionization.

A.1.113.5. 6-Fluoro-7-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine

To a cooled (−78° C.) solution of6-bromo-7-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine (0.500 g,1.82 mmol) in anh. THE (15 mL) is added dropwise a solution of BuLi (1.6M in hexanes, 1.14 mL, 1.82 mmol) and the mixture is further stirred at−78° C., under nitrogen, for 1 min. A solution ofN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.650 g, 2.00 mmol) inanh. THE (10 mL) is then added dropwise and the resulting mixture isstirred at −78° C. for 10 min. The RM is treated dropwise with water andis allowed to warm-up to RT. EtOAc is added and the layers areseparated. The aqueous layer is extracted twice with EtOAc and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=3/7) affords6-fluoro-7-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine as a yellowoil (0.229 g, 59%). LC-MS B: t_(R)=0.83 min; [M+H]⁺=215.12.

A.1.113.6. 6-Bromo-7-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine

A cooled (0° C.) solution of 7-bromo-2,3-dihydrobenzo[b][1,4]dioxin-6-ol(6.260 g, 27.10 mmol, preparation described in A.1.106.4.) in anh. DMF(72 mL) is treated portionwise with sodium hydride (60% dispersion inmineral oil, 1.300 g, 32.50 mmol) and the mixture is stirred at RT,under nitrogen, for 15 min. The cooled (0° C.) mixture is treated withchloromethyl methyl ether (4.12 mL, 54.20 mmol) and is stirred at RT,under nitrogen, for 1.5 h. Water and Et₂O are added and the layers areseparated. The organic layer is washed twice with water, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords6-bromo-7-(methoxymethoxy)-2,3-dihydrobenzo[b][1,4]dioxine as acolorless oil (7.140 g, 96%). LC-MS B: t_(R)=0.90 min; [M+H]⁺=275.01.

A.2. Synthesis of boronic acid derivatives of formula (A4) A.2.1. Methyl2-(2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-(methylthio)phenyl)acetate (1.45 g,5.27 mmol) in anh. DMF (12 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.352 g,5.27 mmol), potassium acetate (2.069 g, 21.10 mmol) and Pd(dppf)Cl₂ (428mg, 0.58 mmol). The RM is heated to 90° C., under nitrogen, for 17 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane to EtOAc)affords methyl2-(2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a pale yellow solid (664 mg, 39%). LC-MS B: t_(R)=1.04 min;[M+H]⁺=323.16.

A.2.1.1. Methyl 2-(4-bromo-2-(methylthio)phenyl)acetate

To a solution of 2-(4-bromo-2-(methylthio)phenyl)acetic acid (1.86 g,7.12 mmol) in anh. DMF (17 mL) at RT are added cesium carbonate (2.901g, 8.90 mmol) and iodomethane (0.667 mL, 10.70 mmol) and the RM isstirred at RT, under nitrogen, for 1 h. Water and Et₂O are added and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords methyl2-(4-bromo-2-(methylthio)phenyl)acetate as a yellow oil (1.45 g, 74%).LC-MS B: t_(R)=0.97 min; no ionization.

A.2.1.2. 2-(4-Bromo-2-(methylthio)phenyl)acetic acid

A mixture of 2-(4-bromo-2-(methylthio)phenyl)acetonitrile (1.76 g, 7.27mmol), water (7 mL), 95% sulfuric acid (7.8 mL) and acetic acid (5.4 mL)is heated to 110° C., under nitrogen, for 4.5 h. The RM is then allowedto cool to RT and is poured onto ice/water. The mixture is extractedtwice with DCM and the combined organic layers are washed with brine,dried over anh. MgSO₄, filtered and concentrated under reduced pressureaffording 2-(4-bromo-2-(methylthio)phenyl)acetic acid as a yellow solid(1.86 g, 98%). LC-MS B: t_(R)=0.82 min; [M+H]⁺=260.70.

A.2.1.3. 2-(4-Bromo-2-(methylthio)phenyl)acetonitrile

A solution of (5-bromo-2-(chloromethyl)phenyl)(methyl)sulfane (2.45 g,9.74 mmol) in MeCN (26 mL) and water (3.4 mL) is treated with sodiumcyanide (646 mg, 12.70 mmol) and the RM is heated to 80° C., undernitrogen, for 16 h. Additional sodium cyanide (238 mg, 4.85 mmol) isthen added and the mixture is heated to 80° C. for 4 h. The RM is thenallowed to cool to RT and is diluted with water. Acetonitrile is removedunder reduced pressure and the RM is extracted twice with DCM. Thecombined organic layers are dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords 2-(4-bromo-2-(methylthio)phenyl)acetonitrileas a pale yellow solid (1.76 g, 75%). LC-MS B: t_(R)=0.95 min;[M+H]⁺=241.81.

A.2.1.4. (5-Bromo-2-(chloromethyl)phenyl)(methyl)sulfane

A cooled (0° C.) mixture of (4-bromo-2-(methylthio)phenyl)methanol (2.31g, 9.91 mmol) and zinc chloride (33.8 mg, 0.248 mmol) in anh. DCM (20mL) is treated dropwise with thionyl chloride (1.45 mL, 19.80 mmol) andthe RM is stirred at 0° C. for 3 h, and then at RT for 15 h. The RM isconcentrated under reduced pressure affording(5-bromo-2-(chloromethyl)phenyl)(methyl)sulfane as a yellow oil (2.45 g,98%). LC-MS B: t_(R)=1.04 min; no ionization.

A.2.1.5. (4-Bromo-2-(methylthio)phenyl)methanol

To a cooled (−78° C.) solution of methyl 4-bromo-2-(methylthio)benzoate(2.87 g, 11.00 mmol) in anh. THE (30 mL) is added dropwise a solution ofdiisobutylaluminum hydride (1 M in toluene, 33.0 mL, 33.0 mmol). Themixture is further stirred at −78° C., under nitrogen, for 15 min and isthen allowed to warm-up to 0° C. Stirring at 0° C. is continued for 15min, and the cooled RM is treated successively with water (31 mL) andwith 2.8 N aq. NaOH (22 mL). The mixture is then allowed to warm-up toRT, EtOAc is added and the layers are separated. The aqueous layer isextracted twice with EtOAc. The combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords(4-bromo-2-(methylthio)phenyl)methanol as a colorless solid (2.31 g,90%). LC-MS B: t_(R)=0.83 min; [M+H]⁺=232.99.

A.2.1.6. Methyl 4-bromo-2-(methylthio)benzoate

To a solution of 4-bromo-2-mercaptobenzoic acid (3.00 g, 12.20 mmol) inanh. DMF (20 mL) at RT is added cesium carbonate (11.952 g, 36.70 mmol)and the mixture is stirred at RT for 15 min. The cooled (0° C.) mixtureis then treated with iodomethane (1.92 mL, 30.60 mmol) and the RM isstirred at RT for 16 h. Water and Et₂O are added and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure affording methyl4-bromo-2-(methylthio)benzoate as a pale orange solid (2.87 g, 90%).LC-MS B: t_(R)=0.96 min; [M+H]⁺=261.06.

A.2.2. Methyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylate

To a solution of methyl 6-bromobenzofuran-2-carboxylate (528 mg, 1.97mmol) in anh. DMF (10 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (505 mg,1.97 mmol), potassium acetate (773 mg, 7.87 mmol) and Pd(dppf)Cl₂ (160mg, 0.21 mmol). The RM is heated to 95° C., under nitrogen, for 17 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylateas a colorless solid (286 mg, 48%). LC-MS B: t_(R)=1.06 min;[M+H]⁺=303.19.

A.2.3. Methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylate

To a solution of methyl 5-bromobenzofuran-2-carboxylate (510 mg, 1.96mmol) in anh. DMF (10 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (503 mg,1.96 mmol), potassium acetate (769 mg, 7.84 mmol) and Pd(dppf)Cl₂ (159mg, 0.21 mmol). The RM is heated to 95° C., under nitrogen, for 17 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-2-carboxylateas a pale yellow oil (298 mg, 50%). LC-MS B: t_(R)=1.06 min;[M+H]⁺=303.16.

A.2.4. Ethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate

To a solution of ethyl 6-bromobenzofuran-3-carboxylate (430 mg, 1.60mmol) in anh. DMF (10 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (410 mg,1.60 mmol), potassium acetate (627 mg, 6.39 mmol) and Pd(dppf)Cl₂ (130mg, 0.17 mmol). The RM is heated to 95° C., under nitrogen, for 17 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords ethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylateas a colorless solid (238 mg, 47%). LC-MS B: t_(R)=1.12 min;[M+H]⁺=317.23.

A.2.5. Methyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxylate

To a solution of methyl 6-bromo-1H-indole-3-carboxylate (500 mg, 1.97mmol) in anh. DMF (10 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (505 mg,1.97 mmol), potassium acetate (773 mg, 7.87 mmol) and Pd(dppf)Cl₂ (160mg, 0.21 mmol). The RM is heated to 95° C., under nitrogen, for 17 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-3-carboxylateas a colorless solid (186 mg, 31%). LC-MS B: t_(R)=0.96 min;[M+H]⁺=302.25.

A.2.6. Ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylate

To a solution of ethyl 2-(4-bromophenyl)acrylate (500 mg, 1.86 mmol) inanh. DMF (10 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (478 mg,1.86 mmol), potassium acetate (731 mg, 7.45 mmol) and Pd(dppf)Cl₂ (151mg, 0.20 mmol). The RM is heated to 95° C., under nitrogen, for 16 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (heptane/EtOAc=7/3) affordsethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylateas a colorless oil (128 mg, 23%). LC-MS B: t_(R)=1.08 min;[M+H]⁺=303.21.

A.2.7. Ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

To a solution of ethyl 2-(4-bromo-2-ethoxyphenyl)propanoate (359 mg,1.19 mmol) in anh. DMF (5 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (306 mg,1.19 mmol), potassium acetate (468 mg, 4.77 mmol) and Pd(dppf)Cl₂ (97mg, 0.13 mmol). The RM is heated to 95° C., under nitrogen, for 17 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateas a colorless oil (249 mg, 60%). LC-MS B: t_(R)=1.13 min;[M+H]⁺=349.30.

A.2.7.1. Ethyl 2-(4-bromo-2-ethoxyphenyl)propanoate

To a cooled (−78° C.) solution of lithium diisopropylamide (1.0 M inTHE/hexanes, 7.80 mL, 7.80 mmol) in anh. THE (15 mL) is added dropwise asolution of ethyl 2-(4-bromo-2-ethoxyphenyl)acetate (2.01 g, 7.76 mmol)in anh. THE (5 mL), and the RM is further stirred at −78° C., undernitrogen, for 30 min. Iodomethane (0.745 mL, 10.10 mmol) is then addedto the previous mixture and stirring is continued at −78° C. for 10 min,and then at 0° C. for 30 min. The RM is then treated dropwise with sat.aq. NH₄Cl and is allowed to warm-up to RT. Water and EtOAc are added andthe layers are separated. The aq. layer is further extracted with EtOAcand the combined organic layers are dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC(heptane/EtOAc=4/1) affords ethyl 2-(4-bromo-2-ethoxyphenyl)propanoateas a colorless solid. LC-MS B: t_(R)=1.06 min; [M+H]⁺=301.09.

A.2.7.2. Ethyl 2-(4-bromo-2-ethoxyphenyl)acetate

To a solution of 2-(4-bromo-2-hydroxyphenyl)acetic acid (2.00 g, 8.66mmol) in anh. DMF (35 mL) at RT are added cesium carbonate (5.641 g,17.30 mmol) and iodoethane (2.44 mL, 30.30 mmol) and the RM is stirredat RT, under nitrogen, for 16 h. Water and Et₂O are added and the layersare separated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(heptane/EtOAc=7/3) affords ethyl 2-(4-bromo-2-ethoxyphenyl)acetate as apale yellow oil (2.01 g, 81%). LC-MS B: t_(R)=1.03 min; [M+H]+=287.14.

A.2.8.2-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aceticacid

Following the procedure described for the synthesis of A.2.7., using2-(4-bromo-2-ethoxyphenyl)acetic acid, the title compound is obtained asa beige solid. LC-MS B: t_(R)=0.91 min; [M+H]⁺=307.27.

A.2.8.1. 2-(4-Bromo-2-ethoxyphenyl)acetic acid

Ethyl 2-(4-bromo-2-ethoxyphenyl)acetate (4538 mg, 16.6 mmol) isdissolved in ethanol (30 mL), NaOH 10% (27.7 mL, 73.1 mmol) is added andthe mixture is stirred overnight at RT. The mixture is treated bydropwise addition of HCl 37% (6.37 mL, 76.3 mmol), extracted with 60 mLDCM then twice with 30 mL of EtOAc, dried over MgSO₄ and evaporatedunder vacuum, affording the title compound as a pale yellow solid (2.5g, 99%). LC-MS B: t_(R)=0.84 min; no ionization

A.2.8.2. Ethyl 2-(4-bromo-2-ethoxyphenyl)acetate

Following the procedure described for A.2.7.2., using4-bromo-2-hydroxyphenylacetic acid and iodoethane, the title compound isobtained as a clear oil. LC-MS B: t_(R)=1.03 min; [M+H]⁺=287.18.

A.2.9.5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)thiophene-2-carboxylicacid

Lithium diisopropylamide solution (2.0 M in TH/hexanes, 2.53 mL, 5.05mmol) is added dropwise to a solution of3-(trifluoromethyl)thiophene-2-carboxylic acid (330 mg, 1.68 mmol) inTHE (7 mL) at −78° C. The RM is stirred for 30 min at −78° C. then at 0°C. for 10 min. Back at −78° C., a solution of2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.771 mL, 3.7mmol) in THE (15 mL) is added dropwise and the RM is slowly allowed towarm to RT overnight. HCl 0.5N (20 mL) is added and the mixture isextracted with EtOAc. The combined organic layers are washed with brine,dried over MgSO₄ and the solvent is removed. The crude product ispurified by FC (DCM/MeOH 1:0 to 19:1) to afford the title compound as alight orange solid (443 mg, 82%). LC-MS A: t_(R)=0.59 min; noionization.

A.2.9.1. 3-(Trifluoromethyl)thiophene-2-carboxylic acid

To a −78° C. solution of 3-(trifluoromethyl)thiophene (0.4 mL, 3.68mmol) in dry THE (10 mL) is added dropwise a solution of BuLi (1.38M inhexane, 2.93 mL, 4.05 mmol) and the RM is stirred for 30 min. The RM isthen poured over an excess of freshly crushed dry ice carbon dioxide.Once the RM is back at RT, HCl 1N is added until pH<3 and the mixture isextracted with DCM (3×). The organic layer is dried over MgSO₄ andconcentrated under vacuum, affording the title compound as a pale yellowsolid (0.72 g, quantitative). LC-MS A: t_(R)=0.69 min; no ionization.

A.2.10.3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylicacid

The title compound is prepared according to the synthesis of A.2.9.using 3-ethoxythiophene-2-carboxylic acid. LC-MS A: t_(R)=0.48 min;[M+H]⁺=217.07 (boronic acid, from hydrolysis of the pinacol ester on theLC-MS-column).

A.2.11.5-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-tetrazole

A mixture of2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(500 mg, 1.83 mmol), azidotributyltin(IV) (0.768 mL, 2.75 mmol), and drytoluene (4 mL) is heated at 180° C. for 1 h in a sealed MW vial under MWirradiation. The mixture is cooled to RT, treated with HCl 0.1N andextracted with EtOAc. The organic layer is dried over MgSO₄ andconcentrated under vacuum. The residue is purified via FC, eluting witha gradient from Heptane:EtOAc 100:0 to 10:90. This affords the titlecompound as a white solid (135 mg, 23%). LC-MS B: t_(R)=0.94 min;[M+H]⁺=317.26.

A.2.11.1.2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A solution of2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(1.50 g, 6.12 mmol), K₂CO (1.69 g, 12.2 mmol) in DMF (4 mL) andiodoethane (0.596 mL, 7.34 mmol) is heated at 120° C. for 30 min. The RMis cooled down to RT, partitioned between DCM and 1N NaHCO₃. The aqueouslayer is re-extracted with DCM, the combined organics are dried (MgSO₄),and concentrated under reduced pressure. This affords the title compoundas a beige solid (1.31 g, 78%). LC-MS B: t_(R)=1.06 min;[M+CH3CN+H]⁺=315.26.

A.2.12.2-(Difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

To a solution of 4-bromo-2-(difluoromethoxy)benzoic acid (1.00 g, 3.56mmol) in DMF (20 mL) are added at RT bis(pinacolato)diboron (1.355 g,5.34 mmol), KOAc (1.047 g, 10.7 mmol) and Pd(dppf)Cl₂ (208 mg, 0.285mmol). The RM is stirred at 100° C. for 17 h, then cooled to RT andfiltered through a pad of celite, washing with EtOAC. The filtrate iswashed with water and the aqueous layer is extrated (×2) with EtOAc.Organic layers are combined, washed with brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The residue ispurified by FC eluting with DCM to afford the title compound as anorange solid (846 mg, 76%). LC-MS A: t_(R)=0.37 min; [M+H]⁺=313.11.

Following the procedure described for the synthesis of A.2.12. describedabove, the following boronic acid derivatives are synthesized, startingfrom the corresponding halides (see table 3).

TABLE 3 Boronic acid derivatives A.2.13.-A.2.16. MS Data t_(R) [min] m/zNo. Compound (LC-MS) [M + H]⁺ A.2.13.2-Cyclobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 0.91 (A) 319.112-yl)benzoic acid A.2.14. Methyl2-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2- 0.96 (A) 309.18dioxaborolan-2-yl)benzoate A.2.15.5-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 0.82 (B)290.10 [1,2,4-]oxadiazol-3-ol A.2.16.1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 0.77 (A)275.27 1,2-dihydro-3H-indazol-3-one

A.2.17.2-Fluoro-6-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

The title compound is prepared according to the procedure described forA.2.12. starting with 4-bromo-2-fluoro-6-propylbenzoic acid. LC-MS E:t_(R)=0.48 min; [M−H]⁺=307.11.

A.2.17.1. 4-Bromo-2-fluoro-6-propylbenzoic acid

To a solution of 4-bromo-2,6-difluorobenzoic acid (5.00 g, 21.1 mmol) inTHE (50 mL) at 0° C. is added dropwise over 30 min n-propylmagnesiumbromide (2M in THF, 21.6 mL, 43.2 mmol). The RM is allowed to reach RTand stirred for 17 h, then quenched carefully at 0° C. with MeOH (10mL). After stirring for 5 min, the solvent is removed under reducedpressure. The residue is partitioned between EtOAc and 2N HCl. Theaqueous phase is re-extracted with EtOAc (2×). The combined org. phasesare washed with water, brine, dried over MgSO₄, filtered andconcentrated. The residue is purified by FC (heptane/EtOAc 100:0 to70:30) to afford the title compound as a white solid (4.45 g, 81%).LC-MS A: t_(R)=0.84 min; no ionization.

A.2.18.2-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)aceticacid

A solution of ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate(1.285 g, 3.82 mmol) in EtOH (15 mL) is treated with NaOH 10% (7.64 mL,19.1 mmol) and the RM is stirred at 50° C. for 30 min. The RM is cooledto RT and diluted with EtOAc. HCl 2N (15 mL) is added to reach acidic pH(<1). The aqueous layer is extracted twice with EtOAc. The resultingorganic phase is dried over MgSO₄ and concentrated, affording the titlecompound as an orange paste (1.10 g, 90%). LC-MS A: t_(R)=0.80 min;[M+H]⁺=323.12.

A.2.18.1. Ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate

A solution of2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.47 g,12.5 mmol) in anhydrous DMF (50 mL) is treated successively with cesiumcarbonate (6.10 g, 18.7 mmol) and ethyl bromoacetate (1.48 mL, 13.1mmol). The RM is stirred at RT for 1 h. Water is added, and the mixtureis extracted with Et₂O (×3). The combined organic layers are then washedsuccessively with water (×2) and brine, dried over MgSO₄, filtered, andconcentrated under reduced pressure to afford the pure product as acolorless oil (1.46 g, 77%). LC-MS A: t_(R)=0.94 min; [M+H]⁺=351.18.

A.2.19.(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycine

To a solution of methyl(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycinate(207 mg, 0.61 mmol) in THF/H2O (4:1) (5 mL) is added LiOH·H2O (51 mg,1.21 mmol) and the RM is stirred at RT for 2 h. The mixture is treatedwith HCl 1N (1 mL) and extracted with EtOAc, dried over MgSO₄ andconcentrated, affording the title compound as a brown oil (0.151 g,78%). LC-MS A: t_(R)=0.82 min; [M+H]⁺=322.07.

A.2.19.1. Methyl(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycinate

The title compound is prepared according to the procedure described forA.2.12., starting with methyl (4-bromo-2-ethoxyphenyl)glycinate. LC-MSA: t_(R)=0.93 min; [M+H]⁺=336.28.

A.2.19.2. Methyl (4-bromo-2-ethoxyphenyl)glycinate

To a solution of 4-bromo-2-ethoxyaniline (0.60 g, 2.64 mmol) in DMF (2.5mL) is added DiPEA (0.673 mL, 3.96 mmol) followed by methyl bromoacetate(0.275 mL, 2.9 mmol). The mixture is stirred at 90° C. for 1 h in themicrowave apparatus. The DMF is evaporated under high vacuum and theresidue is purified by FC, eluting with Hept/EtOAc 1:0 to 17:3 affordingthe title compound as a dark red oil (0.71 g, 94%). LC-MS A: t_(R)=0.89min; [M+H]⁺=288.08.

A.2.20.3-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-[1,2,4]oxadiazol-5(4H)-one

The title compound is prepared according to the procedure described forA.2.12., starting with3-(4-bromo-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one. LC-MS A:t_(R)=0.89 min; [M+H]⁺=333.06.

A.2.20.1. 3-(4-Bromo-2-ethoxyphenyl)-[1,2,4]oxadiazol-5(4H)-one

A solution of 4-bromo-2-ethoxy-N′-hydroxybenzimidamide (1.395 g, 5.38mmol), 1,1′-carbonyldiimidazole (1.31 g, 8.08 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (1.23 mL, 8.08 mmol) in dioxane (20mL) is stirred at 90° C. for 4 h30 min. Once at RT, the productprecipitated upon addition of HCl 1M. Dioxane is partially evaporatedvia N2 stream prior to filtering off the solid under vacuum, washingwith water. The title compound is obtained as a white solid (1.375 g,90%). LC-MS A: t_(R)=0.81 min, [M+MeCN]⁺=325.89.

A.2.20.2. 4-Bromo-2-ethoxy-N′-hydroxybenzimidamide

A suspension of 4-bromo-2-ethoxybenzonitrile (1.50 g, 6.5 mmol),hydroxylamine hydrochloride (913 mg, 13 mmol) and NaHCO₃ (1.365 g, 16.3mmol) in water (1.32 mL) and EtOH (26.6 mL) is stirred in a sealed tubeat 90° C. for 3 h. Once at RT, the product precipitated from the r×n mixupon addition of water. The solid is filtered off under high vacuum,washing with water and some Et₂O. A first crop of pure title compound(947 mg) is thus obtained as white solid. The filtrate is extracted withEtOAc. The organic layer is then washed twice with brine, dried overMgSO₄, filtered and concentrated. The residue is purified by FC(hept/EtOAc 5:5) to yield another crop of the pure title compound as awhite solid (448 mg), merged with the first batch from precipitation.The title compound is obtained as a white solid (1.395 g, 83%). LC-MS A:t_(R)=0.53 min, [M+H]⁺=259.03.

A.2.21.3-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoicacid

The title compound is prepared according to the procedure described forA.2.12., starting with 3-(4-bromo-2-ethoxyphenoxy)propanoic acid. LC-MSB: t_(R)=0.89 min; [M+H]⁺=337.32.

A.2.21.1. 3-(4-Bromo-2-ethoxyphenoxy)propanoic acid

A MW vial is charged with 4-bromo-2-ethoxyphenol (1300 mg, 5.98 mmol),H2O (5 mL), NaOH 32% (1.332 mL, 14.38 mmol) and 3-chloropropionic acid(674 mg, 6.08 mmol). It is sealed and irradiated at 120° C., for 40 minat high energy level. The RM is diluted in water and pH is decreased topH9 with HCl 2N then is extracted twice with EtOAc. The basic aqueouslayer is then acidified to pH2 and extracted twice with EtOAc, thecombined organic extracts are washed with water, brine, dried overMgSO₄, filtered and evaporated to dryness, yielding the title compoundas a a white powder (0.448 g, 56%). LC-MS B: t_(R)=0.89 min;[M+H]⁺=289.10.

A.2.22. Methyl(E)-3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acrylate

The title compound is prepared according to the procedure described forA.2.9. starting with methyl (E)-3-(3-ethoxythiophen-2-yl)acrylate. LC-MSA: t_(R)=1.02 min; [M+H]⁺=339.14.

A.2.22.1. Methyl (E)-3-(3-ethoxythiophen-2-yl)acrylate

A suspension of 3-ethoxythiophene-2-carbaldehyde (2.90 g, 18.6 mmol),methyl bromoacetate (3.07 mL, 33.4 mmol), and triphenylphosphine (7.305g, 27.8 mmol) in aq saturated NaHCO₃ (100 mL) is stirred at RT for 5 h.THE (30 mL) is added and the RM is stirred overnight at RT. It is thenextracted twice with DCM. The combined organic layers are dried overMgSO₄, filtered, and concentrated under vacuum. The crude is purified byFC (Hept/EtOAc 9:1) to afford the title compound as a dark orange oil(2.9 g, 100%). LC-MS A: t_(R)=0.69 min; [M+MeCN]⁺=198.26.

A.2.23.3-(3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)propanoicacid

To a solution of methyl(E)-3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acrylate[A.2.22.] (250 mg, 0.786 mmol) in MeOH (15 mL) is added Pd/C 5% wet (50mg). Then the vessel is inertized with N₂ and flushed with H₂. Themixture is placed in a autoclave and it is stirred overnight at RT under4 Bar of H₂, then for 1d at 50° C. under 4 bar of H₂. After filtrationon whatman filter, NaOH 10% (1.18 mL, 11.8 mmol) is added and the RM isstirred for 1 h at RT. It is then treated with HCl 2N until pH<1 andextracted twice with EtOAc. The organic layer is dried over MgSO₄ andconcentrated, to afford the title compound as a dark yellow oil (287 mg,74%). LC-MS A: t_(R)=0.86 min; [M+H]⁺=327.09.

A.2.24. Methyl2-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate

A suspension of methyl 2-(3-ethoxythiophen-2-yl)acetate (815 mg, 4.07mmol), bis(pinacolato)diboron (633 mg, 2.44 mmol),(1,5-cyclooctadiene)(methoxy)iridium(I) dimer (28.9 mg, 0.0437 mmol) and4,4′-di-tert-butyl-2,2′-dipyridyl (26.8 mg, 0.0999 mmol) in THE (19.3mL) is degassed with a nitrogen stream for 15 min and then stirred at80° C. overnight. The RM is concentrated under reduced pressure and theresidue is purified by FC (Hept to Hept/EtOAc 9:1) to afford the titlecompound as a colourless oil which crystallized upon standing (908 mg,68%). LC-MS B: t_(R)=1.03 min, [M+H]⁺=327.14.

A.2.24.1. Methyl 2-(3-ethoxythiophen-2-yl)acetate

Silver benzoate (1800 mg, 7.78 mmol) is added portionwise to a solutionof 2-diazo-1-(3-ethoxythiophen-2-yl)ethan-1-one (2025 mg, 10.3 mmol) andTEA (4.31 mL, 31 mmol) in MeOH (52.7 mL) and the RM is stirred at RT for2 h. It is then diluted with EtOAc and filtered over celite. Thefiltrate is washed twice with sat. aq. NaHCO₃ and once with brine. Theorganic layer is dried over MgSO₄, filtered and concentrated. Theresidue is purified by FC (Hept to Hept/EtOAc 95:5) to yield the titlecompound as a light yellow oil (817 mg, 40%). LC-MS B: t_(R)=0.86 min,[M+H]⁺=201.14.

A.2.24.2. 2-Diazo-1-(3-ethoxythiophen-2-yl)ethan-1-one

A solution of 3-ethoxythiophene-2-carboxylicacid (2500 mg, 14.1 mmol) inDCM (120 mL) is treated with thionyl chloride (1.56 mL, 21.1 mmol),dropwise. The RM is stirred at RT overnight, it is then concentrated invacuo, and the residue is dissolved in MeCN (80 mL). TEA (2.2 mL, 15.8mmol) is added dropwise and the solution is cooled down to 0° C.(Trimethylsilyl)diazomethane (2M solution, 15 mL, 30 mmol) is addeddropwise and the RM is stirred at RT for 2d. It is then carefullyquenched by dropwise addition of AcOH, until no more bubbling isobserved. The RM is then concentrated and the residue is partitionedbetween EtOAc and water. The organic layer is then washed with sat. aq.NaHCO₃ and with brine, dried (MgSO₄) and concentrated. The residue ispurified by FC (Hept to Hept/EtOAc 8:2) to yield the title compound asan intense yellow solid (2.028 g, 73%). LC-MS B: t_(R)=0.78 min,[M+H]⁺=197.15.

A.2.25. Ethyl2-((2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)-2-oxoacetate

The title compound is prepared according to the procedure described forA.2.12., starting with ethyl2-((4-bromo-2-ethoxyphenyl)amino)-2-oxoacetate. LC-MS A: t_(R)=0.98 min;[M+H]⁺=364.21.

A.2.25.1. Ethyl 2-((4-bromo-2-ethoxyphenyl)amino)-2-oxoacetate

To a solution of 4-bromo-2-ethoxyaniline (1.10 g, 4.84 mmol) in DCM (35mL) is added TEA (0.748 mL, 5.32 mmol) at RT. The RM is cooled to 0° C.and ethyl oxalyl chloride (0.61 mL, 5.32 mmol) is added dropwise. The RMis stirred for 30 min at 0° C. then allowed to warm to RT and stirredfor 30 min. The RM is partitioned between EtOAc and sat. aq. NaHCO₃. Thetwo layers are separated and the organic layers washed with water, brinethen dried over MgSO₄, filtered and solvent removed under vacuo,affording the title compound as a brown solid (1.52 g, 99%). LC-MS A:t_(R)=0.92 min; [M+MeCN]⁺=316.04.

A.2.26.2-Butoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

The title compound is prepared according to the procedure described forA.2.12., starting with 4-bromo-2-butoxy-6-fluorobenzoic acid. LC-MS A:t_(R)=0.92 min; [M+H]⁺=339.21.

A.2.26.1. 4-Bromo-2-butoxy-6-fluorobenzoic acid

Methyl 4-bromo-2-butoxy-6-fluorobenzoate (1246 mg, 3.94 mmol) isdissolved in EtOH (15 mL). NaOH 32% (1.82 mL, 19.7 mmol) is added andthe RM is heated up to 60° C. for 1 h. it is then cooled to RT anddiluted with EtOAc. HCl 2N (10 mL) is added to reach acidic pH (<2). Theaq. layer is extracted twice with EtOAc. The resulting organic phase isdried over MgSO₄ and concentrated, affording the title compound as awhite solid. LC-MS E: t_(R)=0.52 min; [M−H]⁺=290.89.

A.2.26.2. Methyl 4-bromo-2-butoxy-6-fluorobenzoate

To a solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1.00 g, 4.02mmol) in DMF (10 mL), is added Cs₂CO₃ (2.62 g, 8.03 mmol) followed by1-iodobutane (0.685 mL, 6.02 mmol). The RM is stirred at 120° C. for 2 hunder MW irradiation. The RM is concentrated under reduced pressure, theresidue is partitioned between DCM and water. The aqueous layer isre-extracted with DCM, the combined organics are dried (MgSO₄), andconcentrated under reduced pressure. Purification by FC (Hept/EtOAc 1:0to 19:1) affords the title compound as a colourless oil (1.24 g, 99%).LC-MS A: t_(R)=0.98 min; [M+H]⁺=306.84.

A.2.27. Methyl2-(2-hydroxyethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The title compound is prepared according to the procedure described forA.2.12., starting with methyl 4-bromo-2-(2-hydroxyethoxy)benzoate. LC-MSB: t_(R)=0.89 min; [M+H]⁺=323.26.

A.2.27.1. Methyl 4-bromo-2-(2-hydroxyethoxy)benzoate

NaH (101 mg, 4.2 mmol) is added portionwise to a 0° C. solution ofmethyl 4-bromo-2-hydroxybenzoate (500 mg, 2.1 mmol) in DMF (5 mL). TheRM is stirred for a few minutes at 0° C., then 2-bromoethanol (0.235 mL,3.15 mmol) is added and the RM is stirred at 90° C. for 2 h45, thencooled to RT. Water is added to the RM and it is extracted twice withEtOAc. The combined organic layers are washed with brine, dried overMgSO₄, filtered and concentrated under reduced pressure. The residue ispurified by FC (heptane/EtOAc, 1:0 to 6:4), affording the title compoundas a colorless oil (358 mg, 62%). LC-MS B: t_(R)=0.77 min;[M+H]⁺=275.14.

A.2.28.7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one

The title compound is prepared according to the procedure described forA.2.24., starting with 2,3-dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one.LC-MS B: t_(R)=0.51 min; [M+H]⁺=215.41 (mass from boronic acid frompinacol ester cleavage during LC-MS analysis).

A.2.28.1. 2,3-Dihydro-5H-thieno[3,2-e][1,4]dioxepin-5-one

A MW vial is charged with K₂CO (623 mg, 4.5 mmol), methyl3-hydroxythiophene-2-carboxylate (250 mg, 1.5 mmol) and DMF (5 mL). TheRM is stirred for a few minutes then 2-bromoethanol (0.146 mL, 1.95mmol) is added, the vial is capped and heated at 100° C. for 2 h underMW irradiation. 2-Bromoethanol (0.0319 mL, 0.45 mmol) is added and theRM is stirred at 90° C. overnight, under thermal conditions. Once at RT,water is added and the RM is extracted thrice with EtOAc. The combinedorganic layers are dried over MgSO₄, filtered and concentrated underreduced pressure, affording the crude title compound as a brownish solid(338 mg, quantitative). LC-MS B: t_(R)=0.61 min; [M+H]⁺=170.94.

A.2.29. Methyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate

To a solution of2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (390 mg,1.48 mmol) in DMF (15 mL) at RT is added K₂CO (427 mg, 3.03 mmol). TheRM is stirred 15 min at 60° C. then methyl 2-bromopropionate (0.2 mL,1.77 mmol) is added and the RM is stirred overnight at 60° C. The RM iscooled to RT, concentrated in vacuo, and the residue is partitionedbetween EtOAc and water. The organic layer is washed once more withwater, then brine, dried over MgSO₄, filtered and evaporated to dryness,affording the title compound as a pale yellow oil which crystallizesupon standing (447 mg, 86%). LC-MS B: t_(R)=1.04 min; [M+H]⁺=351.08.

A.2.30.3-(3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)oxetan-3-ol

The title compound is prepared according to the procedure described forA.2.9., starting with 3-(3-methoxythiophen-2-yl)oxetan-3-ol. LC-MS A:t_(R)=0.78 min; [M−H₂O]⁺=295.12.

A.2.30.1. 3-(3-Methoxythiophen-2-yl)oxetan-3-ol

To a stirred solution of 3-methoxythiophene (1.00 g, 8.58 mmol) andN,N,N′,N′-tetramethylethylenediamine (1.55 mL, 10.3 mmol) in Et₂O (30mL) is added BuLi (1.6M in Hexane, 6.4 mL, 10.3 mmol) dropwise at 0° C.The RM is stirred at RT for 30 min, then 3-oxetanone (0.761 mL, 12.9mmol) is added dropwise and the RM is stirred at RT for 35 min, thendiluted with water, the aqueous layer is extracted three times withEtOAc and the combined organic layers are dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue is purified by FC (Heptto Hept/EtOAc 8:2) to give the title compound as a light-yellow oil(1.123 g, 70%). LC-MS A: t_(R)=0.53 min; [M−H₂O]⁺=169.04.

A.2.31.3-Ethoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobut-3-ene-1,2-dione

3-Ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione (335 mg, 0.807mmol) and 4-iodophenylboronic acid, pinacol ester (298 mg, 0.904 mmol)are dissolved in DMF (4 mL) with N₂ bubbling for 5 min.Trans-Benzyl(chloro)bis(triphenylphosphine)palladium(II) (36.7 mg,0.0484 mmol) and CuI (15.4 mg, 0.0807 mmol) are added and the RM isstirred at RT for 3 h., then filtered over a microglass filter,concentrated under vacuum and purified by FC (Hept:EtOAc 100:0 to 80:20)to obtain the title compound as a yellow solid (127 mg, 48%). LC-MS A:t_(R)=0.97 min; [M+MeCN]⁺=370.07.

A.2.32.2,6-Dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

The title compound is prepared according to the procedure described forA.2.12., starting with 4-bromo-2,6-dimethoxybenzoic acid. LC-MS B:t_(R)=0.84 min; [M+H]⁺=309.10.

A.2.33. Methyl2-ethoxy-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The title compound is prepared according to the procedure described forA.2.12., starting with methyl 4-bromo-2-ethoxy-6-methoxybenzoate. LC-MSB: t_(R)=1.04 min; [M+H]⁺=337.18.

A.2.33.1. Methyl 4-bromo-2-ethoxy-6-methoxybenzoate

To 4-bromo-2-ethoxy-6-methoxybenzoic acid (3080 mg, 11.2 mmol) in DMF(30 mL) is added portionise Cs₂CO₃ (4742 mg, 14.6 mmol), followed bymethyl iodide (0.836 mL, 13.4 mmol), dropwise. The RM is stirred at RTfor 2 h, then water is added and the mixture is extracted with Et₂O. Theorganic layer is successively washed with water and brine, dried overMgSO₄ and concentrated under reduced pressure. The residue is purifiedby FC (Hept/EtOAc from 1:0 to 1:1) to afford the product as a whitesolid (2.87 g, 89%). LC-MS B: t_(R)=0.96 min; [M+H]⁺=288.99.

A.2.33.2. 4-Bromo-2-ethoxy-6-methoxybenzoic acid

4-Bromo-2-ethoxy-6-methoxybenzaldehyde (2950 mg, 11.4 mmol) is suspendedin t-BuOH (48 mL) and a solution of sodium chlorite (2574 mg, 22.8 mmol)and sodium phosphate monobasic monohydrate (7935 mg, 56.9 mmol) in water(24 mL) is added dropwise. After complete addition, 2-methyl-2-butene(10.2 mL, 91.1 mmol) is added. The RM is stirred at RT for 30 min thenconcentrated under reduced pressure. The residue is suspended in water,acidified with 1N aq HCl and extracted 3 time with Et₂O. The combinedextracts are washed with 1N aq NaOH (3 times). The combined aqueouslayers are acidified with 6N aq HCl and extracted 3 times with EtOAc.The organic extracts are dried over MgSO₄, filtered and concentratedunder reduced pressure, to provide the title compound as a pale yellowsolid (3.08 g, 98%). LC-MS B: t_(R)=0.79 min; [M+H]⁺=274.91.

A.2.33.3. 4-Bromo-2-ethoxy-6-methoxybenzaldehyde

To a solution of 4-bromo-2-hydroxy-6-methoxybenzaldehyde (2880 mg, 12.5mmol) in DMF (30 mL) is added cesium carbonate (4874 mg, 15 mmol),followed by iodoethane (1.1 mL, 13.7 mmol). The RM is stirred at RTovernight. Water is added and the aqueous layer is extracted with Et₂O(3×). The combined organic layers are washed with water, dried overMgSO₄, concentrated. Purification by FC (Hept/EtOAc from 1:0 to 1:1)affords the title compound as a white solid (2.95 g, 91%). LC-MS B:t_(R)=0.90 min; [M+H]⁺=258.95.

A.2.34. Ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methylpropanoate

The title compound is prepared according to the procedure described forA.2.12., starting with ethyl2-(4-bromo-2-ethoxyphenoxy)-2-methylpropanoate. LC-MS B: t_(R)=1.13 min;[M+H]⁺=379.22.

A.2.34.1. Ethyl 2-(4-bromo-2-ethoxyphenoxy)-2-methylpropanoate

The title compound is prepared according to the procedure described forA.2.18.1., using 4-bromo-2-ethoxyphenol and ethyl 2-bromoisobutyrate.LC-MS B: t_(R)=1.09 min: [M+H]⁺=331.09.

A.2.35. Methyl2-(2-ethoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetate(1.370 g, 4.71 mmol) in anh. DMF (12 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.207 g,4.71 mmol), potassium acetate (1.847 g, 18.80 mmol) and Pd(dppf)Cl₂ (383mg, 0.51 mmol). The RM is heated to 90° C., under nitrogen, overnight.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords methyl2-(2-ethoxy-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a colorless solid (0.970 g, 61%). LC-MS B: t_(R)=1.09 min;[M+H]⁺=339.21.

A.2.35.1. Methyl 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetate

To a solution of 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetic acid (1.440g, 5.20 mmol) in anh. DMF (15 mL) at RT are added cesium carbonate(2.117 g, 6.50 mmol) and iodomethane (0.48 mL, 7.80 mmol) and the RM isstirred at RT, under nitrogen, for 15 min. Water and Et₂O are added andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords methyl2-(4-bromo-2-ethoxy-6-fluorophenyl)acetate as a colorless oil (1.370 g,91%). LC-MS B: t_(R)=1.01 min; [M+H]⁺=290.99.

A.2.35.2. 2-(4-Bromo-2-ethoxy-6-fluorophenyl)acetic acid

A mixture of 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetonitrile (1.440 g,5.58 mmol), water (5 mL), 95% sulfuric acid (6 mL) and acetic acid (7mL) is heated to 110° C., under nitrogen, for 3 h. The RM is thenallowed to cool to RT and is poured onto ice/water. The mixture isextracted twice with DCM and the combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure affording crude 2-(4-bromo-2-ethoxy-6-fluorophenyl)acetic acidas a colorless solid (1.440 g, 93%). LC-MS B: t_(R)=0.88 min; noionization.

A.2.35.3. 2-(4-Bromo-2-ethoxy-6-fluorophenyl)acetonitrile

A solution of 5-bromo-2-(chloromethyl)-1-ethoxy-3-fluorobenzene (2.860g, 10.10 mmol) in MeCN (27 mL) and water (3.5 mL) is treated with sodiumcyanide (669 mg, 13.10 mmol) and the RM is heated to 80° C., undernitrogen, overnight. The RM is then allowed to cool to RT and is dilutedwith water. Acetonitrile is removed under reduced pressure and themixture is extracted twice with DCM. The combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords2-(4-bromo-2-ethoxy-6-fluorophenyl)acetonitrile as a colorless solid(1.440 g, 55%). LC-MS B: t_(R)=0.97 min; no ionization.

A.2.35.4. 5-Bromo-2-(chloromethyl)-1-ethoxy-3-fluorobenzene

A cooled (0° C.) mixture of (4-bromo-2-ethoxy-6-fluorophenyl)methanol(2.180 g, 8.75 mmol) and zinc chloride (29.8 mg, 0.219 mmol) in anh. DCM(17 mL) is treated dropwise with thionyl chloride (1.28 mL, 17.50 mmol)and the RM is stirred at 0° C. for 2 h. The RM is concentrated underreduced pressure affording crude5-bromo-2-(chloromethyl)-1-ethoxy-3-fluorobenzene as a pale pink oil(2.330 g, 99%). LC-MS B: t_(R)=1.07 min; no ionization.

A.2.35.5. (4-Bromo-2-ethoxy-6-fluorophenyl)methanol

To a cooled (−78° C.) solution of methyl4-bromo-2-ethoxy-6-fluorobenzoate (3.150 g, 11.40 mmol) in anh. THE (30mL) is added dropwise a solution of diisobutylaluminum hydride (1 M intoluene, 34.1 mL, 34.1 mmol). The mixture is further stirred at −78° C.,under nitrogen, for 15 min and is then allowed to warm-up to 0° C.Stirring at 0° C. is continued for 45 min, and the cooled RM is thentreated successively with water (35 mL) and 2.8 N aq. NaOH (25 mL). Themixture is allowed to warm-up to RT and is further stirred for 30 min.The resulting mixture is filtered over celite, washing with THE. EtOAcand water are added and the layers are separated. The aqueous layer isextracted twice with EtOAc and the combined organic layers are driedover anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to EtOAc) affords(4-bromo-2-ethoxy-6-fluorophenyl)methanol as a colorless solid (2.680 g,95%). LC-MS B: t_(R)=0.84 min; no ionization.

A.2.35.6. Methyl 4-bromo-2-ethoxy-6-fluorobenzoate

To a solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (2.930 g,11.20 mmol) in anh. DMF (14 mL) at RT are added successively cesiumcarbonate (3.642 g, 11.20 mmol) and iodoethane (0.90 mL, 11.20 mmol) andthe RM is stirred at RT for 30 min. Additional cesium carbonate (3.729g, 11.40 mmol) and iodoethane (0.92 mL, 11.40 mmol) are then added andthe RM is stirred at RT for 20 min. Water and Et₂O are added and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords methyl4-bromo-2-ethoxy-6-fluorobenzoate as a yellow oil (3.150 g,quantitative). LC-MS B: t_(R)=0.97 min; [M+H]⁺=277.08.

A.2.36. Isopropyl2-(2-isopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

Bis(pinacolato)diboron (1618 mg, 6.31 mmol) followed by potassiumacetate (2477 mg, 25.2 mmol) are added to a RT solution of isopropyl2-(4-bromo-2-isopropoxyphenyl)acetate (2046 mg, 6.31 mmol) in DMF (25mL). The RM is purged with N₂ anddichloro(1,1′-bis(diphenylphosphino)ferrocene) palladium (II) (513 mg,0.694 mmol) is added. The RM is heated at 95° C. overnight, then cooledto RT, filtered over a pad of celite and rinsed with Et₂O. Water andEt₂O are added, and the two layers are separated. The aqueous layer isextracted with Et₂O (3×). The combined organic layers are washed withwater (2×), brine, dried over MgSO₄, filtered and evaporated in vacuum.The residue is purified by FC (Hept:EtOAc 100:0 to 70:30) to afford thetitle compound as a light green oil (1.604 g, 70%). LC-MS B: t_(R)=1.14min; [M+H]⁺=363.25.

A.2.36.1. Isopropyl 2-(4-bromo-2-isopropoxyphenyl)acetate

To 4-bromo-2-hydroxyphenylacetic acid (2000 mg, 8.22 mmol) in DMF (25mL) is added cesium carbonate (5359 mg, 16.4 mmol) and 2-bromopropane(2.73 mL, 28.8 mmol) at 0° C. The RM is warmed up to RT and stirred for1 h, then heated to 45° C. and stirred for 24 h. Water is added and theresulting mixture is extracted with Et₂O (3×). Organic layers are mixedand washed with additional water (2×), brine, then dried over a phaseseparator and concentrated under vacuum. The residue is purified by FC(Hept:EtOAc 100:0 to 75:25) to yield the title compound as a light greenoil (2.046 g, 79%). LC-MS B: t_(R)=1.10 min; [M+H]⁺=315.11.

A.2.37. Methyl2-(2-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-isobutylphenyl)acetate (2.271 g,7.13 mmol) in anh. DMF (25 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.828 g,7.13 mmol), potassium acetate (2.798 g, 28.50 mmol) and Pd(dppf)Cl₂ (579mg, 0.78 mmol). The RM is heated to 95° C., under nitrogen, for 16 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords methyl2-(2-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a yellow oil (1.822 g, 77%). LC-MS B: t_(R)=1.13 min; [M+H]⁺=333.24.

A.2.37.1. Methyl 2-(4-bromo-2-isobutylphenyl)acetate

To a solution of 2-(4-bromo-2-isobutylphenyl)acetic acid (2.457 g, 8.64mmol) in anh. DMF (30 mL) at RT are added cesium carbonate (5.633 g,17.30 mmol) and iodomethane (1.09 mL, 17.30 mmol) and the RM is stirredat RT, under nitrogen, for 1 h. Water and Et₂O are added and the layersare separated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords methyl2-(4-bromo-2-isobutylphenyl)acetate as a clear oil (2.271 g, 92%). LC-MSB: t_(R)=1.06 min; no ionization.

A.2.37.2. 2-(4-Bromo-2-isobutylphenyl)acetic acid

A mixture of 2-(4-bromo-2-isobutylphenyl)acetonitrile (2.162 g, 8.41mmol), water (8 mL), 95% sulfuric acid (9 mL) and acetic acid (6 mL) isheated to 110° C., under nitrogen, overnight. The RM is then allowed tocool to RT and is poured onto ice/water. The mixture is extracted twicewith DCM and the combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressureaffording crude 2-(4-bromo-2-isobutylphenyl)acetic acid as an amber oil(2.457 g, quantitative). LC-MS B: t_(R)=0.96 min; no ionization.

A.2.37.3. 2-(4-Bromo-2-isobutylphenyl)acetonitrile

A solution of 4-bromo-1-(chloromethyl)-2-isobutylbenzene (2.381 g, 9.00mmol) in MeCN (24 mL) and water (3 mL) is treated with sodium cyanide(597 mg, 11.70 mmol) and the RM is heated to 80° C., under nitrogen,overnight. The RM is then allowed to cool to RT and is diluted withwater. Acetonitrile is removed under reduced pressure and the RM isextracted twice with DCM. The combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords2-(4-bromo-2-isobutylphenyl)acetonitrile as a clear oil (2.162 g, 95%).LC-MS B: t_(R)=1.05 min; no ionization.

A.2.37.4. 4-Bromo-1-(chloromethyl)-2-isobutylbenzene

A cooled (0° C.) mixture of (4-bromo-2-isobutylphenyl)methanol (2.192 g,8.83 mmol) and zinc chloride (30.1 mg, 0.221 mmol) in anh. DCM (20 mL)is treated dropwise with thionyl chloride (1.29 mL, 17.70 mmol) and theRM is stirred at 0° C. for 4 h. The RM is concentrated under reducedpressure affording crude 4-bromo-1-(chloromethyl)-2-isobutylbenzene as alight pink oil (2.381 g, quantitative). LC-MS B: t_(R)=1.13 min; noionization.

A.2.37.5. (4-Bromo-2-isobutylphenyl)methanol

To a cooled (−78° C.) solution of methyl 4-bromo-2-isobutylbenzoate(2.712 g, 9.71 mmol) in anh. THE (60 mL) is added dropwise a solution ofdiisobutylaluminum hydride (1 M in toluene, 29.1 mL, 29.1 mmol). Themixture is further stirred at −78° C., under nitrogen, for 15 min and isthen allowed to warm-up to 0° C. Stirring at 0° C. is continued for 30min, and the cooled RM is treated successively with water (1 mL), 2.8 Naq. NaOH (1 mL) and water (3 mL). The mixture is then allowed to warm-upto RT and is further stirred for 30 min. The resulting mixture isfiltered over celite, washing with THE and the filtrate is concentratedto dryness under reduced pressure. EtOAc and water are added and thelayers are separated. The aqueous layer is extracted twice with EtOAcand the combined organic layers are dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords (4-bromo-2-isobutylphenyl)methanol (2.192 g,93%). LC-MS B: t_(R)=0.96 min; no ionization.

A.2.37.6. Methyl 4-bromo-2-isobutylbenzoate

To a solution of 4-bromo-2-isobutylbenzoic acid (4.254 g, 14.30 mmol) inanh. DMF (50 mL) at RT are added successively cesium carbonate (9.304 g,28.60 mmol) and iodomethane (1.80 mL, 28.60 mmol) and the RM is stirredat RT for 1 h. Water and Et₂O are added and the layers are separated.The aqueous layer is extracted twice with Et₂O and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl 4-bromo-2-isobutylbenzoate as a lightyellow oil (3.462 g, 89%). LC-MS B: t_(R)=1.11 min; no ionization.

A.2.37.7. 4-Bromo-2-isobutylbenzoic acid

To a cooled (0° C.) solution of 4-bromo-2-fluorobenzoic acid (5.000 g,22.40 mmol) in anh. THE (40 mL) is added dropwise a solution ofisobutylmagnesium bromide (2.0 M in Et₂O, 33.5 mL, 67.0 mmol) and the RMis further stirred at RT, under nitrogen, overnight. MeOH (10 mL) isthen added dropwise to the cooled (0° C.) reaction mixture that isfurther stirred at 0° C. for 5 min. The resulting mixture is thenconcentrated to dryness under reduced pressure and the residue ispartitioned between EtOAc and 2 M aq. HCl. The layers are separated, andthe aq. layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords 4-bromo-2-isobutylbenzoic acid as a lightyellow solid (4.254 g, 74%). LC-MS B: t_(R)=0.97 min; no ionization.

A.2.38. Methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-(trifluoromethoxy)phenyl)acetate(1.896 g, 5.58 mmol) in anh. DMF (25 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.432 g,5.58 mmol), potassium acetate (2.192 g, 22.30 mmol) and Pd(dppf)Cl₂ (454mg, 0.61 mmol). The RM is heated to 95° C., under nitrogen, overnight.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)phenyl)acetateas a green oil (1.574 g, 78%). LC-MS B: t_(R)=1.09 min; [M+H]⁺=361.13.

A.2.38.1. Methyl 2-(4-bromo-2-(trifluoromethoxy)phenyl)acetate

To a solution of 2-(4-bromo-2-(trifluoromethoxy)phenyl)acetic acid(2.000 g, 6.56 mmol) in anh. DMF (30 mL) at RT are added cesiumcarbonate (4.277 g, 13.10 mmol) and iodomethane (0.82 mL, 13.10 mmol)and the RM is stirred at RT, under nitrogen, for 1 h. Water and Et₂O areadded and the layers are separated. The aqueous layer is extracted twicewith Et₂O and the combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords methyl2-(4-bromo-2-(trifluoromethoxy)phenyl)acetate as a clear oil (1.896 g,92%). LC-MS B: t_(R)=1.01 min; no ionization.

A.2.39. Methyl2-(2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-(difluoromethoxy)phenyl)acetate(800 mg, 2.71 mmol) in anh. DMF (20 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (695 mg,2.71 mmol), potassium acetate (1.064 g, 10.80 mmol) and Pd(dppf)Cl₂ (220mg, 0.29 mmol). The RM is heated to 90° C., under nitrogen, overnight.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords methyl2-(2-(difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a yellow oil (367 mg, 40%). LC-MS B: t_(R)=1.03 min; no ionization.

A.2.39.1. Methyl 2-(4-bromo-2-(difluoromethoxy)phenyl)acetate

To a solution of 2-(4-bromo-2-(difluoromethoxy)phenyl)acetic acid (3.560g, 12.70 mmol) in anh. DMF (20 mL) at RT are added cesium carbonate(6.191 g, 19.00 mmol) and iodomethane (0.95 mL, 15.20 mmol) and the RMis stirred at RT, under nitrogen, for 1 h. Water and Et₂O are added andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords methyl2-(4-bromo-2-(difluoromethoxy)phenyl)acetate as a colorless oil (2.390g, 64%). LC-MS B: t_(R)=0.94 min; no ionization.

A.2.39.2. 2-(4-Bromo-2-(difluoromethoxy)phenyl)acetic acid

To a mixture of 2-(4-bromo-2-(difluoromethoxy)phenyl)acetonitrile (3.460g, 13.20 mmol) in EtOH (100 mL) and water (100 mL) at RT is addedpotassium hydroxide (2.222 g, 39.60 mmol) and the RM is heated atreflux, under nitrogen, overnight. The RM is then allowed to cool to RTand ethanol is removed under reduced pressure. The resulting mixture istreated with 1 M aq. HCl and is extracted twice with DCM. The combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure affording crude2-(4-bromo-2-(difluoromethoxy)phenyl)acetic acid as an off-white solid(3.560 g, 96%). LC-MS B: t_(R)=0.82 min; no ionization.

A.2.39.3. 2-(4-Bromo-2-(difluoromethoxy)phenyl)acetonitrile

A solution of 4-bromo-1-(chloromethyl)-2-(difluoromethoxy)benzene (3.890g, 14.30 mmol) in MeCN (38 mL) and water (5 mL) is treated with sodiumcyanide (913 mg, 18.60 mmol) and the RM is heated to 85° C., undernitrogen, for 3 h. The RM is then allowed to cool to RT and is dilutedwith water. Acetonitrile is removed under reduced pressure and themixture is extracted twice with DCM. The combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to EtOAc) affords2-(4-bromo-2-(difluoromethoxy)phenyl)acetonitrile as a pale yellow solid(3.560 g, 95%). LC-MS B: t_(R)=0.92 min; no ionization.

A.2.39.4. 4-Bromo-1-(chloromethyl)-2-(difluoromethoxy)benzene

A cooled (0° C.) mixture of (4-bromo-2-(difluoromethoxy)phenyl)methanol(3.580 g, 14.10 mmol) and zinc chloride (48.2 mg, 0.354 mmol) in anh.DCM (28 mL) is treated dropwise with thionyl chloride (2.06 mL, 28.30mmol) and the RM is stirred at 0° C. for 3.5 h. The RM is concentratedunder reduced pressure affording crude4-bromo-1-(chloromethyl)-2-(difluoromethoxy)benzene as a colorless oil(3.890 g, quantitative). LC-MS B: t_(R)=1.00 min; no ionization.

A.2.39.5. (4-Bromo-2-(difluoromethoxy)phenyl)

To a cooled (0° C.) solution of 4-bromo-2-(difluoromethoxy)benzaldehyde(3.820 g, 15.20 mmol) in anh. MeOH (75 mL) is added portionwise sodiumborohydride (1.727 g, 45.70 mmol) and the mixture is further stirred at0° C., under nitrogen, for 1 h. Methanol is then removed under reducedpressure. DCM and water are added and the layers are separated. Theaqueous layer is extracted twice with DCM and the combined organiclayers are dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=1/1)affords (4-bromo-2-(difluoromethoxy)phenyl)methanol as a colorless oil(3.890 g, quantitative). LC-MS B: t_(R)=0.81 min; no ionization.

A.2.39.6. 4-Bromo-2-(difluoromethoxy)benzaldehyde

To a cooled (0° C.) solution of 4-bromo-2-hydroxybenzaldehyde (5.000 g,24.40 mmol) in MeCN (135 mL) and water (135 mL) is added potassiumhydroxide (27.355 g, 488.00 mmol). The mixture is stirred at RT for 30min, and is then cooled to −30° C. Diethyl(bromodifluoromethyl)phosphonate (13.283 g, 48.80 mmol) is added in oneportion to the cooled mixture and stirring is then continued at RT for 2h. Et₂O is added, the layers are separated and the aqueous layer isfurther extracted with Et₂O. The combined organic layers aresuccessively washed with 1 M aq. NaOH, water and brine and are thendried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords4-bromo-2-(difluoromethoxy)benzaldehyde as a pale yellow solid (3.820 g,62%). LC-MS B: t_(R)=0.92 min; no ionization.

A.2.40. Methyl2-(2-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-propylphenyl)acetate (2.380 g, 8.78mmol) in anh. DMF (20 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.251 g,8.78 mmol), potassium acetate (3.446 g, 35.10 mmol) and Pd(dppf)Cl₂ (714mg, 0.96 mmol). The RM is heated to 90° C., under nitrogen, for 16 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords methyl2-(2-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a colorless oil (2.230 g, 80%). LC-MS B: t_(R)=1.10 min;[M+H]⁺=319.31.

A.2.40.1. Methyl 2-(4-bromo-2-propylphenyl)acetate

To a solution of 2-(4-bromo-2-propylphenyl)acetic acid (2.770 g, 10.80mmol) in anh. DMF (20 mL) at RT are added cesium carbonate (5.265 g,16.20 mmol) and iodomethane (1.02 mL, 16.20 mmol) and the RM is stirredat RT, under nitrogen, for 1 h. Water and Et₂O are added and the layersare separated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords methyl2-(4-bromo-2-propylphenyl)acetate as a yellow oil (2.380 g, 81%). LC-MSB: t_(R)=1.04 min; no ionization.

A.2.40.2. 2-(4-Bromo-2-propylphenyl)acetic acid

A mixture of 2-(4-bromo-2-propylphenyl)acetonitrile (2.570 g, 10.80mmol), water (10 mL), 95% sulfuric acid (11.5 mL) and acetic acid (8 mL)is heated to 110° C., under nitrogen, for 3 h. The RM is then allowed tocool to RT and is poured onto ice/water. The mixture is extracted twicewith DCM and the combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressureaffording crude 2-(4-bromo-2-propylphenyl)acetic acid as a pale greysolid (3.390 g, quantitative). LC-MS B: t_(R)=0.91 min; no ionization.

A.2.40.3. 2-(4-Bromo-2-propylphenyl)acetonitrile

A solution of 4-bromo-1-(chloromethyl)-2-propylbenzene (2.980 g, 12.00mmol) in MeCN (32 mL) and water (3.9 mL) is treated with sodium cyanide(767 mg, 15.60 mmol) and the RM is heated to 80° C., under nitrogen,overnight. The RM is then allowed to cool to RT and is diluted withwater. Acetonitrile is removed under reduced pressure and the RM isextracted twice with DCM. The combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to EtOAc) affords2-(4-bromo-2-propylphenyl)acetonitrile as a pale yellow oil (2.570 g,90%). LC-MS B: t_(R)=1.02 min; no ionization.

A.2.40.4. 4-Bromo-1-(chloromethyl)-2-propylbenzene

A cooled (0° C.) mixture of (4-bromo-2-propylphenyl)methanol (2.650 g,11.60 mmol) and zinc chloride (39.4 mg, 0.289 mmol) in anh. DCM (23 mL)is treated dropwise with thionyl chloride (1.69 mL, 23.10 mmol) and theRM is stirred at 0° C. for 3 h, and then at RT overnight. The RM isconcentrated under reduced pressure affording crude4-bromo-1-(chloromethyl)-2-propylbenzene as a grey oil (2.98 g,quantitative). LC-MS B: t_(R)=1.10 min; no ionization.

A.2.40.5. (4-Bromo-2-propylphenyl)methanol

To a cooled (−78° C.) solution of methyl 4-bromo-2-propylbenzoate (3.300g, 12.80 mmol) in anh. THE (60 mL) is added dropwise a solution ofdiisobutylaluminum hydride (1 M in toluene, 38.5 mL, 38.5 mmol). Themixture is further stirred at −78° C., under nitrogen, for 15 min and isthen allowed to warm-up to 0° C. Stirring at 0° C. is continued for 45min, and the cooled RM is treated successively with water (1.5 mL), 2.8N aq. NaOH (1.5 mL) and water (4 mL). The mixture is then allowed towarm-up to RT and stirring was continued for 30 min. The resultingmixture was filtered over celite washing with THE and the filtrate wasconcentrated to dryness under reduced pressure. Purification by FC (fromheptane to heptane/EtOAc=1/1) affords (4-bromo-2-propylphenyl)methanolas a colorless oil (2.650 g, 90%). LC-MS B: t_(R)=0.91 min; noionization.

A.2.40.6. Methyl 4-bromo-2-propylbenzoate

To a solution of 4-bromo-2-propylbenzoic acid (3.590 g, 14.80 mmol) inanh. DMF (30 mL) at RT are added successively cesium carbonate (9.623 g,29.50 mmol) and iodomethane (1.86 mL, 29.50 mmol) and the RM is stirredat RT for 16 h. Water and Et₂O are added and the layers are separated.The aqueous layer is extracted twice with Et₂O and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords methyl 4-bromo-2-propylbenzoate as acolorless oil (3.300 g, 87%). LC-MS B: t_(R)=1.05 min; no ionization.

A.2.40.7. 4-Bromo-2-propylbenzoic acid

To a cooled (0° C.) solution of 4-bromo-2-fluorobenzoic acid (5.000 g,22.40 mmol) in anh. THE (40 mL) is added dropwise a solution ofpropylmagnesium bromide (2.0 M in THF, 33.50 mL, 67.00 mmol) and the RMis further stirred at RT, under nitrogen, overnight. MeOH (10 mL) isthen added dropwise to the cooled (0° C.) reaction mixture that isfurther stirred at 0° C. for 5 min. The resulting mixture is thenconcentrated to dryness under reduced pressure and the residue ispartitioned between EtOAc and 2 M aq. HCl. The layers are separated, andthe aq. layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/2) affords 4-bromo-2-propylbenzoic acid as a colorlesssolid (3.590 g, 66%). LC-MS B: t_(R)=0.93 min; no ionization.

A.2.41. Methyl2-(2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-ethylphenyl)acetate (900 mg, 3.24mmol) in anh. DMF (15 mL) are added at RT4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (832 mg, 3.24mmol), potassium acetate (1.274 g, 13.00 mmol) and Pd(dppf)Cl₂ (264 mg,0.35 mmol). The RM is heated to 90° C., under nitrogen, overnight. TheRM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=4/1) affords methyl2-(2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a light yellow oil (708 mg, 72%). LC-MS B: t_(R)=1.05 min;[M+H]⁺=305.22.

A.2.41.1. Methyl 2-(4-bromo-2-ethylphenyl)acetate

To a solution of 2-(4-bromo-2-ethylphenyl)acetic acid (2.118 g, 8.05mmol) in anh. DMF (20 mL) at RT are added cesium carbonate (5.246 g,16.10 mmol) and iodomethane (1.01 mL, 16.10 mmol) and the RM is stirredat RT, under nitrogen, for 1 h. Water and Et₂O are added and the layersare separated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=7/3) affords methyl2-(4-bromo-2-ethylphenyl)acetate as a light yellow oil (2.043 g, 99%).LC-MS B: t_(R)=0.99 min; no ionization.

A.2.41.2. 2-(4-Bromo-2-ethylphenyl)acetic acid

A mixture of 2-(4-bromo-2-ethylphenyl)acetonitrile (1.859 g, 7.99 mmol),water (7.5 mL), 95% sulfuric acid (8.3 mL) and acetic acid (5.8 mL) isheated to 110° C., under nitrogen, for 4 h. The RM is then allowed tocool to RT and is poured onto ice/water. The mixture is extracted twicewith DCM and the combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressureaffording crude 2-(4-bromo-2-ethylphenyl)acetic acid as an amber solid(2.118 g, quantitative). LC-MS B: t_(R)=0.85 min; no ionization.

A.2.41.3. 2-(4-Bromo-2-ethylphenyl)acetonitrile

A solution of 4-bromo-1-(chloromethyl)-2-ethylbenzene (2.050 g, 8.34mmol) in MeCN (24 mL) and water (3 mL) is treated with sodium cyanide(553 mg, 10.80 mmol) and the RM is heated to 80° C., under nitrogen,overnight. The RM is then allowed to cool to RT and is diluted withwater. Acetonitrile is removed under reduced pressure and the RM isextracted twice with DCM. The combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords2-(4-bromo-2-ethylphenyl)acetonitrile as a colorless solid (1.859 g,99%). LC-MS B: t_(R)=0.95 min: no ionization.

A.2.41.4. 4-Bromo-1-(chloromethyl)-2-ethylbenzene

A cooled (0° C.) mixture of (4-bromo-2-ethylphenyl)methanol (1.854 g,8.30 mmol) and zinc chloride (28.3 mg, 0.208 mmol) in anh. DCM (20 mL)is treated dropwise with thionyl chloride (1.21 mL, 16.60 mmol) and theRM is stirred at 0° C. for 2 h. The RM is concentrated under reducedpressure affording crude 4-bromo-1-(chloromethyl)-2-ethylbenzene as alight purple oil (2.050 g, quantitative). LC-MS B: t_(R)=1.04 min; noionization.

A.2.41.5. (4-Bromo-2-ethylphenyl)methanol

To a cooled (−78° C.) solution of methyl 4-bromo-2-ethylbenzoate (2.219g, 9.01 mmol) in anh. THE (60 mL) is added dropwise a solution ofdiisobutylaluminum hydride (1 M in toluene, 27.0 mL, 27.0 mmol). Themixture is further stirred at −78° C., under nitrogen, for 15 min and isthen allowed to warm-up to 0° C. Stirring at 0° C. is continued for 45min, and the cooled RM is treated successively with water (1 mL), 2.8 Naq. NaOH (1 mL) and water (3 mL). The mixture is then allowed to warm-upto RT and is further stirred for 30 min. The resulting mixture isfiltered over celite, washing with THE and the filtrate is concentratedto dryness under reduced pressure. EtOAc and water are added and thelayers are separated. The aqueous layer is extracted twice with EtOAcand the combined organic layers are dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords (4-bromo-2-ethylphenyl)methanol (1.854 g,96%). LC-MS B: t_(R)=0.84 min; no ionization.

A.2.41.6. Methyl 4-bromo-2-ethylbenzoate

To a solution of 4-bromo-2-ethylbenzoic acid (3.003 g, 12.80 mmol) inanh. DMF (30 mL) at RT are added cesium carbonate (8.355 g, 25.60 mmol)and iodomethane (1.61 mL, 25.60 mmol) and the RM is stirred at RT for 1h. Water and Et₂O are added and the layers are separated. The aqueouslayer is extracted twice with Et₂O and the combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl 4-bromo-2-ethylbenzoate as a clear oil(2.735 g, 88%). LC-MS B: t_(R)=1.02 min; no ionization.

A.2.41.7. 4-Bromo-2-ethylbenzoic acid

To a cooled (0° C.) solution of 4-bromo-2-fluorobenzoic acid (5.000 g,22.40 mmol) in anh. THE (40 mL) is added dropwise a solution ofethylmagnesium bromide (1.0 M in THF, 67.1 mL, 67.1 mmol) and the RM isfurther stirred at RT, under nitrogen, for 3 h. MeOH (15 mL) is thenadded dropwise to the cooled (0° C.) reaction mixture that is furtherstirred at 0° C. for 5 min. The resulting mixture is then concentratedto dryness under reduced pressure and the residue is partitioned betweenEtOAc and 2 M aq. HCl. The layers are separated, and the aq. layer isextracted twice with EtOAc. The combined organic layers are then washedwith brine, dried over anh. MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=7/3)affords 4-bromo-2-ethylbenzoic acid as a colorless solid (3.003 g, 59%).LC-MS B: t_(R)=0.87 min: no ionization.

A.2.42.2-(2-Propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)aceticacid

To a solution of propyl2-(2-propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate(308 mg, 0.85 mmol) in EtOH (9 mL) is added NaOH (10% aq. Solution, 3.4mL) and the mixture is stirred at RT for 2 h. EtOH is removed in vacuo.pH of the resulting basic aqueous layer is adjusted to pH=3-4 using HCl1N and extracted twice with EtOAc. The combined organic layers arewashed with water, brine, dried over MgSO₄, filtered and solvent isremoved in vacuo, yielding the title compound as a white powder (0.238g, 87%). LC-MS A: t_(R)=0.88 min; [M+H]⁺=321.08.

A.2.42.1. Propyl2-(2-propoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

The title compound is prepared according to the procedure described forA.2.12., starting with propyl 2-(4-bromo-2-propoxyphenyl)acetate. LC-MSA: t_(R)=1.04 min; [M+H]⁺=363.12.

A.2.42.2. Propyl 2-(4-bromo-2-propoxyphenyl)acetate

To a solution of 4-bromo-2-hydroxyphenylacetic acid (1.50 g, 6.37 mmol,)in DMF (50 mL) is added 1-iodopropane (1.38 mL, 14 mmol, 2.2 eq) andCs₂CO₃ (6.23 g, 19.1 mmol). The RM is stirred at 100° C. over night,then cooled to RT. Water is added, and the DMF is removed under reducedpressure. The residue is partitioned between EtOAc and water. Theaqueous layer is re-extracted twice with EtOAc. The combined organicextracts are washed with brine, dried (MgSO₄) and concentrated in vacuo.The residue is purified by FC (Hept:EtOAc 100:0 to 90:10), affording thetitle compound as a colourless oil (0.775 g, 39%). LC-MS A: t_(R)=1.00min; [M+H]⁺=315.07.

A.2.43. Methyl3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

To a solution of lithium diisopropylamide (2.0 M inTHF/heptane/ethylbenzene, 10 mL, 9.6 mmol) in THE (20 mL) at −78° C. isadded dropwise a solution of methyl 3-ethylthiophene-2-carboxylate (1123mg, 6.4 mmol) in THE (15 mL). The RM is stirred for 10 min at −78° C.then a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2 mL, 9.6 mmol) in THE (25 mL) is added dropwise, the RM is stirred for20 min at −78° C. then it is allowed to warm to RT and stirred for 1.5h. HCl 2N (25 mL, 51.2 mmol) is added to the RM at 0° C., and it isstirred for 5 min. The mixture is extracted with EtOAc (3 times). Thecombined organic layers are washed with brine, dried over MgSO₄ andconcentrated to dryness, to afford the title compound as an orange oil,crystallizing upon standing (2.00 g, quant.).; LC-MS B: t_(R)=1.10 min;[M+H]⁺=297.27.

A.2.44. Rac-methyl2-(2-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

The title compound is prepared according to the procedure described forA.2.12., starting with rac-methyl 2-(4-bromo-2-propylphenyl)propanoate.LC-MS B: t_(R)=1.14 min; [M+H]⁺=333.25.

A.2.44.1. Rac-methyl 2-(4-bromo-2-propylphenyl)propanoate

To a solution of 2-(4-bromo-2-propylphenyl)acetic acid (A.2.40.2., 2150mg, 8.36 mmol) in anhydrous DMF (10 mL) is added Cs₂CO (5449 mg, 16.7mmol) followed by iodomethane (1.05 mL, 16.7 mmol). The RM is stirred atRT overnight. Water is added and the mixture is extracted with Et₂O(3×). Organic layers are mixed and washed with water (2×), then driedover MgSO₄, filtered and concentrated to dryness. Purification by FC(Hept/EtOAc from 1:0 to 1:1) afforded the title compound as a paleyellow oil (1.60 g, 76%). LC-MS B: t_(R)=1.04 min; no ionization.

A.2.45.3-(2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoicacid

The title compound is prepared according to the procedure described forA.2.12., starting with 3-(4-bromo-2-methoxyphenoxy)propanoic acid. LC-MSB: t_(R)=0.85 min; [M+H]⁺=323.16.

A.2.45.1. 3-(4-Bromo-2-methoxyphenoxy)propanoic acid

To a suspension of NaH (60% in oil, 1431 mg, 35.8 mmol) in DMF (10 mL)is added dropwise 4-bromo-2-methoxyphenol (2850 mg, 13.8 mmol) in DMF(10 mL). After 30 min, 3-bromopropionic acid (2525 mg, 16.5 mmol) in DMF(8 mL) is added dropwise, and the RM is stirred at RT overnight. 2M aqHCl is added carefully and the resulting mixture is extracted with EtOAc(3×). Organic layers are mixed and washed with water (2×), then driedover phase separator and concentrated to dryness. Purification by FC(Hept/EtOAc from 1:0 to 1:1) afforded the title compound as a whitesolid (1.29 g, 34%). LC-MS B: t_(R)=0.78 min; no ionization.

A.2.46.1-(2-Propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylicacid

The title compound is prepared according to the procedure described forA.2.12., starting with1-(4-bromo-2-propylphenyl)cyclopropane-1-carboxylic acid. LC-MS B:t_(R)=1.02 min; [M+MeCN]⁺=372.47.

A.2.46.1. 1-(4-Bromo-2-propylphenyl)cyclopropane-1-carboxylic acid

In a flask containing1-(4-bromo-2-propylphenyl)cyclopropane-1-carbonitrile (465 mg, 1.69mmol) and equipped with a condenser, are added successively H₂O (1.6mL), AcOH (1.2 mL) and H₂SO₄ (1.8 mL). The RM is stirred at 110° C. for3 d, then cooled to RT. The RM is poured into ice water and the mixtureis extracted with DCM (3×). The combined organic layers are washed withNaOH 1N. The basic aqueous layer is extracted once more with EtOAc. Theaqueous layer is acidified till pH2-3 by addition of 2N HCl. This acidicaqueous layer is then extracted twice with EtOAc. These organic layers(acidic extraction) are combined, washed with water, brine, dried overMgSO₄, filtered and concentrated under reduced pressure, affording thetitle compound as a white solid (283 mg, 65%). LC-MS B: t_(R)=0.96 min;no ionization. ¹H NMR (400 MHz, d₆-DMSO) δ: 12.13-12.49 (m, 1H),7.36-7.41 (m, 1H), 7.23-7.33 (m, 1H), 7.13-7.22 (m, 1H), 2.59-2.67 (m,2H), 1.61 (m, 2H), 1.43-1.56 (m, 2H), 1.06-1.15 (m, 2H), 0.81-0.98 (m,3H).

A.2.46.2. 1-(4-Bromo-2-propylphenyl)cyclopropane-1-carbonitrile

To a solution of 2-(4-bromo-2-propylphenyl)acetonitrile (A.3.42.3., 1180mg, 4.81 mmol) in toluene (25 mL) are added at RT under argon1,2-dibromoethane (1.26 mL, 14.4 mmol), benzyltriethylammonium chloride(89.4 mg, 0.385 mmol) and NaOH (1346 mg, 33.6 mmol). The RM is stirredover 2 nights at 110° C., it is then cooled to RT and 1,2-dibromoethane(1.26 mL, 14.4 mmol), benzyltriethylammonium chloride (89.4 mg, 0.385mmol) and NaOH (1346 mg, 33.6 mmol) are added and the RM is stirredovernight at 110° C. Once at RT, the RM is quenched with water andconcentrated in vacuo. The residue is partitioned between EtOAc andwater. The aqueous is extracted once more with EtOAc. The combinedorganic layers are washed with water, brine, dried over MgSO₄, filteredand concentrated in vacuo. The residue is purified by FC (Hept:EtOAc,100:0 to 95:5), affording the title compound as a yellow oil (468 mg37%). LC-MS B: t_(R)=1.06 min; [M+H]⁺=263.92.

A.2.47. Methyl3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

To a solution of methyl 3-hydroxythiophene-2-carboxylate (815 mg, 5.15mmol) in THE (36 mL) cooled at −78° C., lithium diisopropylamide (2.0 Min TH/hexanes, 7.75 mL, 15.5 mmol) is added dropwise. The RM is stirred10 min at −78° C. then a solution of2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.36 mL, 11.3mmol) in THE (12 mL) is added dropwise and the RM is kept stirring 15min at −78° C. then is allowed to warm to RT over 2 h. HCl 1M (42 mL,41.2 mmol) is added to the RM and it is extracted with EtOAc (3*40 mL).The combined organic layers are washed with brine, dried over MgSO₄ andthe solvent is removed in vacuo yielding the title compound as a brownoil which crytallizes upon standing (1.7 g, quant.). LC-MS B: t_(R)=0.86min; no ionization.

A.2.48.2-(2-Ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)aceticacid

A solution of ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate(1.285 g, 3.82 mmol) in EtOH (15 mL) is treated with NaOH 10% (7.64 mL,19.1 mmol) and the RM is stirred at 50° C. for 30 min. The RM is cooledto RT and diluted with EtOAc. HCl 2N (15 mL) is added to reach acidic pH(<1). The aqueous layer is extracted twice with EtOAc. The resultingorganic phase is dried over MgSO₄ and concentrated, affording the titlecompound as an orange paste (1.11 g, 90%). LC-MS A: t_(R)=0.80 min;[M+H]⁺=323.12.

A.2.48.1. Ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate

A solution of2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.47 g,12.5 mmol) in anhydrous DMF (50 mL) is treated successively with Cs₂CO₃(6.10 g, 18.7 mmol) and ethyl bromoacetate (1.48 mL, 13.1 mmol). The RMis stirred at RT for 1 h. Water is added, and the mixture is extractedwith Et2O (×3). The combined organic layers are then washed successivelywith water (×2) and brine, dried over MgSO₄, filtered, and concentratedto dryness under reduced pressure to afford the pure product as acolorless oil (1.46 g, 77%). LC-MS A: t_(R)=0.94 min; [M+H]⁺=351.18.

A.2.49.5-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-[1,2,4]oxadiazol-3-ol

(The title compound is prepared according to the procedure described forA.2.12., starting with5-(4-bromophenyl)-2,3-dihydro-[1,2,4]oxadiazol-3-one. LC-MS A:t_(R)=0.82 min; [M+MeCN]⁺=330.07.

A.2.50. Methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate

The title compound is prepared according to the procedure described forA.2.12., starting with methyl 4-bromo-1H-indole-7-carboxylate. LC-MS A:t_(R)=0.95 min; [M+H]⁺=302.23.

A.2.51.3-(3-Ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)propanoicacid

To a solution of methyl(E)-3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acrylate(250 mg, 0.786 mmol) in MeOH (15 mL) is added Pd/C 5% wet (50 mg). Thenthe vessel is inertized with N₂ and flushed with H₂. The mixture isplaced in a autoclave and it is stirred overnight at RT under 4 bar ofH₂, then for 1d at 50° C. under 4 bar of H₂. After filtration on whatmanfilter, NaOH 10% (1.18 mL, 11.8 mmol) is added and the RM is stirred for1 h at RT. It is then treated with HCl 2N until pH<1 and extracted twicewith EtOAc. The organic layer is dried over MgSO₄ and concentrated, toafford the title compound as a dark yellow oil (287 mg, 74%). LC-MS A:t_(R)=0.86 min; [M+H]⁺=327.09.

A.2.51.1. Methyl(E)-3-(3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acrylate

The title compound is prepared according to the procedure described forA.2.47., starting with methyl (E)-3-(3-ethoxythiophen-2-yl)acrylate.LC-MS A: t_(R)=1.02 min; [M+H]⁺=339.14.

A.2.51.2. Methyl (E)-3-(3-ethoxythiophen-2-yl)acrylate

A suspension of 3-ethoxythiophene-2-carbaldehyde (2.90 g, 18.6 mmol),methyl bromoacetate (3.07 mL, 33.4 mmol), and triphenylphosphine (7.305g, 27.8 mmol) in aq saturated NaHCO₃ (100 mL) is stirred at RT for 5 h.THE (30 mL) is added and the RM is stirred overnight at RT. It is thenextracted twice with DCM. The combined organic layers are dried overMgSO₄, filtered, and concentrated under vacuum. The crude is purified byFC (Hept/EtOAc 9:1) to afford the title compound as a dark orange oil(2.9 g, 100%). LC-MS A: t_(R)=0.69 min; [M+MeCN]⁺=198.26.

A.2.52.2-Ethoxy-6-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

The title compound is prepared according to the procedure described forA.2.12., starting with 4-bromo-2-ethoxy-6-propylbenzoic acid. LC-MS A:t_(R)=0.90 min; [M+H]⁺=335.11.

A.2.52.1. 4-Bromo-2-ethoxy-6-propylbenzoic acid

To 4-bromo-2-fluoro-6-propylbenzoic acid (3430 mg, 13.9 mmol) in DMF (20mL) is added sodium hydride (60% in oil, 1222 mg, 30.5 mmol)portionwise. When the vigorous gas evolution slowed, dry ethanol (0.891mL, 15.3 mmol) in 5 mL of DMF is added and the RM is heated at 100° C.for 1 h. Once cooled, the mixture is poured into water, pH adjusted to 3and then extracted 3 times with EtOAc. The combined org. phases arewashed with water, brine, dried over MgSO₄, filtered and concentrated.The residue is purified by FC (heptane/ethyl acetate from 100:0 to80:20), affording the title compound as an orange solid (2.19 g, 95%).LC-MS A: t_(R)=0.86 min; [M+H]⁺=286.98.

A.2.53.5-(2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-ol

Butyllithium (1.6M in hexane, 1.1 mL, 1.76 mmol) is added dropwise, at−78° C. under nitrogen, to a stirred solution of5-(4-bromo-2-methoxyphenyl) isoxazol-3-ol (158 mg, 0.585 mmol) in dryTHE (4 mL). The RM is stirred at −78° C. for 25 min, thenisopropoxyboronic acid, pinacol ester (0.418 mL, 2.05 mmol) is addeddropwise and the RM is stirred at −78° C. for 45 min then at RT for 40min. The RM is quenched with sat. aq. NH₄Cl and extracted with EtOAc.The organic layer is washed twice with brine, dried over MgSO₄, filteredand concentrated. The residue is purified by FC (Hept:EtOAc 9:1 to 8:2)to afford the expected product as a white solid (42 mg, 23%). LC-MS A:t_(R)=0.86 min, [M+H]⁺=318.14.

A.2.53.1. 5-(4-Bromo-2-methoxyphenyl) isoxazol-3-ol

HCl conc. (6.8 mL) is added dropwise at RT to a stirred suspension of3-(4-bromo-2-methoxyphenyl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide(284 mg, 0.763 mmol) in MeOH (1.7 mL). The RM is stirred at RT for 30min. Water (4 mL) is added and the precipitate is filtered off, washingwith 1.2 mL water to afford the expected product as a white solid (169mg, 82%) LC-MS A: t_(R)=0.79 min, [M+H]⁺=271.99.

A.2.53.2.3-(4-Bromo-2-methoxyphenyl)-3-oxo-N-((tetrahydro-2H-pyran-2-yl)oxy)propanamide

To a solution of ethyl 3-(4-bromo-2-methoxyphenyl)-3-oxopropanoate (971mg, 1.33 mmol) in NMP (15.7 mL) are sequentially added0-(tetrahydro-2H-pyran-2-yl)hydroxylamine (512 mg, 4.19 mmol) and DMAP(433 mg, 3.55 mmol) at RT. The RM is heated to 115° C. and stirredovernight, then cooled to RT. The mixture is partitioned between 40 mLHCl 0.5M (pH 2) and 40 mL EtOAc. The organic layer is washed three timeswith 40 mL NaCl sat. The aqueous layer is reextracted with 40 mL EtOAc.The organic layers are combined, dried over MgSO₄, filtered andconcentrated. The residue is purified by FC (Hept:EtOAc), affording thetitle compound as a white solid (301 mg, 25%). LC-MS A: t_(R)=0.76 min,[M+H]⁺=373.98.

A.2.53.3. Ethyl 3-(4-bromo-2-methoxyphenyl)-3-oxopropanoate

1-(4-bromo-2-methoxyphenyl)ethanone (1.00 g, 4.37 mmol) is dissolved indiethyl carbonate (5.6 mL, 46.2 mmol). NaH (66% suspension in oil, 384mg, 9.6 mmol) is added carefully. The RM is stirred overnight at RT.Water is added carefully and the mixture is extracted two times withEtOAc. The organic layers are washed with water, brine, dried overMgSO₄, filtered and concentrated. The residue is purified by FC(Hept-EtOAc, affording the title compound as a light yellow oil (933 mg,71%). LC-MS A: t_(R)=0.87 min, [M+H]⁺=303.01.

A.2.54. Ethyl2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoacetate

The title compound is prepared according to the procedure described forA.2.12., starting with ethyl 2-(4-bromo-2-ethoxyphenyl)-2-oxoacetate.LC-MS A: t_(R)=0.98 min: [M+H]⁺=349.19.

A.2.54.1. Ethyl 2-(4-bromo-2-ethoxyphenyl)-2-oxoacetate

To a solution of 2-(4-bromo-2-hydroxyphenyl)-2-oxoacetic acid (1.00 g,3.88 mmol) and K₂CO (1.605 g,) in DMF (10 mL) is added iodethane (0.799mL, 9.69 mmol) and the RM is stirred at 50° C. for 2 d. K₂CO₃ (1.605 g,11.6 mmol) and iodethane (0.799 mL, 9.69 mmol) are added and the RM isstirred at 60° C. for 20 h. The RM is filtered, rinsed with DCM andconcentrated under reduced. The residue is purified by FC (Hept/EtOAc1:0 to 4:1) to afford the title compound as a beige solid (0.921 g,79%). LC-MS A: t_(R)=0.92 min; [M+H]⁺=303.03.

A.2.55.1-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinazolin-2(1H)-one

The title compound is prepared according to the procedure described forA.2.12., starting with 7-bromo-1-methyl-3,4-dihydroquinazolin-2(1H)-one.LC-MS A: t_(R)=0.80 min; [M+H]⁺=289.18.

A.2.56. Ethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylate

To a solution of ethyl 6-bromobenzofuran-3-carboxylate (1.850 g, 6.87mmol) in anh. DMF (20 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.763 g,6.87 mmol), potassium acetate (2.699 g, 27.50 mmol) and Pd(dppf)Cl₂ (559mg, 0.75 mmol). The RM is heated to 95° C., under nitrogen, overnight.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords ethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxylateas a light yellow solid (1.528 g, 70%). LC-MS B: t_(R)=1.11 min;[M+H]⁺=317.23.

A.2.57.3-Ethoxy-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobut-3-ene-1,2-dione

3-Ethoxy-4-(tributylstannyl)cyclobut-3-ene-1,2-dione (335 mg, 0.807mmol) and 4-iodophenylboronic acid, pinacol ester (298 mg, 0.904 mmol)are dissolved in DMF (4 mL) with N₂ bubbling for 5 min.Trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (36.7 mg,0.0484 mmol) and CuI (15.4 mg, 0.0807 mmol) are added and the RM isstirred at RT for 3 h., then filtered over a microglass filter,concentrated under vacuum and purified by FC (Hept.:EtOAc 100:0 to80:20) to obtain the title compound as a yellow solid (127 mg, 48%).LC-MS A: t_(R)=0.97 min; [M+MeCN]⁺=370.07.

A.2.58.5-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazol-3-ol

Butyllithium solution 2.5M (2 mL, 5.03 mmol) is added dropwise, at −78°C. under nitrogen, to a stirred solution of 5-(4-bromo-2-ethoxyphenyl)isoxazol-3-ol (286 mg, 1.01 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.733 mL, 3.52mmol) in dry THE (15 mL). The RM is stirred at −78° C. for 15 min thenwater is added at −78° C. and mixture is left stirring at RT for 40 min.A saturated solution of NH₄Cl is added and the aqueous phase isextracted with EtOAc. The organic layer is washed twice with brine, thenit is dried over MgSO₄, filtered and concentrated. The crude residue ispurified by FC (Hept to Hept/EtOAc 1:1), to afford the title compound asa white solid (390 mg, quant.). LC-MS B: t_(R)=0.98 min; [M+H]⁺=332.34 &[M+H+MeCN]⁺=373.55

A.2.58.1. 5-(4-bromo-2-ethoxyphenyl) isoxazol-3-ol

To a solution of ethyl 3-(4-bromo-2-ethoxyphenyl)propiolate (1017 mg,3.42 mmol) in EtOH (30 mL), Hydroxylamine hydrochloride (721 mg, 10.3mmol) is added followed by dropwise addition of NaOH 10% (6.85 mL, 18.8mmol); the RM is stirred overnight at RT. The solvent is distilled offunder reduced pressure, the residue obtained is suspended in water, andthe suspension is adjusted to pH 2-3 with a 2N aqueous HCl solution. Theresultant solid is filtered off to afford the title compound as a whitesolid (380 mg, 39%). LC-MS B: t_(R)=0.91 min; [M+H]⁺=284.17/286.25.

A.2.58.2. Ethyl 3-(4-bromo-2-ethoxyphenyl)propiolate

A CO_(2 (gas)) inlet is set up in the reaction apparatus and CO₂ isbubbled continuously into a stirred solution of((4-bromo-2-ethoxyphenyl)ethynyl)trimethylsilane (1950 mg, 6.56 mmol) inDMSO (20 mL). Cesium fluoride (1220 mg, 7.87 mmol) is added and the RMis stirred at RT for 2 h. CO₂ bubbling is stopped and iodoethane (0.639mL, 7.87 mmol) is added dropwise. The RM is further stirred at RT for 3h and then poured into water. The aqueous phase is extracted twice withEtOAc and the combined organic layers are washed back with water andfinally brine. The organic phase is dried over MgSO₄ and concentrated todryness. Purification by FC (Hept:EtOAc 100:0 to 85:15) yields the tilecompound as an orange oil (1.017 g, 52%). LC-MS B: t_(R)=1.08 min;[M+H]⁺=297.20/299.23.

A.2.58.3. ((4-Bromo-2-ethoxyphenyl)ethynyl)trimethylsilane

To a solution of 4-bromo-2-ethoxy-1-iodobenzene (2120 mg, 6.48 mmol) inTHE (20 mL) are added TEA (2.71 mL, 19.5 mmol), ethynyltrimethylsilane(1.12 mL, 7.78 mmol) and copper iodide (61.7 mg, 0.324 mmol). The RM isdegassed and put under argon 3 times. Thentrans-dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) isadded and the RM is degassed a last time, put under argon and stirred at70° C. for 16 h. The mixture is cooled to RT and partitioned betweenEtOAc and water. The organic layer is washed with brine, dried overNa₂SO₄, filtered and the solvent is evaporated. The resulting residue ispurified by FC (Hept:EtOAc 100:0 to 90:10) to yield the title compoundas an orange oil (1.95 g, 100%). LC-MS B: t_(R)=1.18 min; no ionization;¹H NMR (400 MHz, d6-DMSO) δ: 7.31 (d, J=8.2 Hz, 1H), 7.24 (d, J=1.6 Hz,1H), 7.10 (dd, J₁=1.7 Hz, J₂=8.1 Hz, 1H), 4.09 (q, J=7.0 Hz, 2H), 1.33(t, J=6.8 Hz, 3H), 0.22 (s, 9H).

A.2.59.3-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-[1,2,4]oxadiazol-5(4H)-one

The title compound is prepared according to the procedure described forA.2.12., starting with 3-(4-bromophenyl)-[1,2,4]oxadiazol-5(4H)-one.LC-MS B: t_(R)=0.90 min: [M+MeCN]⁺=330.12.

A.2.60. Methyl2-(2-chloro-6-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-chloro-6-ethylphenyl)acetate (254mg, 0.87 mmol) in anh. DMF (10 mL) are added at RT4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (223 mg, 0.87mmol), potassium acetate (342 mg, 3.48 mmol) and Pd(dppf)Cl₂ (70 mg,0.095 mmol). The RM is heated to 90° C., under nitrogen, for 5.5 h. TheRM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords methyl2-(2-chloro-6-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a pale yellow oil (126 mg, 43%). LC-MS B: t_(R)=1.14 min;[M+H]⁺=339.35.

A.2.60.1. Methyl 2-(4-bromo-2-chloro-6-ethylphenyl)acetate

To a solution of 2-(4-bromo-2-chloro-6-ethylphenyl)acetic acid (259 mg,0.93 mmol) in anh. DMF (9 mL) at RT are added cesium carbonate (456 mg,1.40 mmol) and iodomethane (70 μL, 1.12 mmol) and the RM is stirred atRT, under nitrogen, for 30 min. Water and Et₂O are added and the layersare separated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords methyl2-(4-bromo-2-chloro-6-ethylphenyl)acetate as a pale yellow solid (254mg, 93%). LC-MS B: t_(R)=1.03 min; no ionization.

A.2.60.2. 2-(4-Bromo-2-chloro-6-ethylphenyl)acetic acid

A mixture of 2-(4-bromo-2-chloro-6-ethylphenyl)acetonitrile (511 mg,1.98 mmol), potassium hydroxide (333 mg, 5.93 mmol) in EtOH (15 mL) andwater (15 mL) is heated to 110° C., under nitrogen, for 24 h. The RM isthen allowed to cool to RT and is concentrated under reduced pressure. 1M aq. HCl and DCM are successively added, the layers are then separatedand the aqueous layer is extracted twice with DCM. The combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure affording crude2-(4-bromo-2-chloro-6-ethylphenyl)acetic acid as an off-white solid (259mg). LC-MS B: t_(R)=0.90 min; no ionization.

A.2.60.3. 2-(4-Bromo-2-chloro-6-ethylphenyl)acetonitrile

A solution of 5-bromo-1-chloro-2-(chloromethyl)-3-ethylbenzene (740 mg,2.76 mmol) in MeCN (14 mL) and water (2 mL) is treated with sodiumcyanide (176 mg, 3.59 mmol) and the RM is heated to 80° C., undernitrogen, overnight. The RM is then allowed to cool to RT and is dilutedwith water. Acetonitrile is removed under reduced pressure and themixture is extracted twice with DCM. The combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords2-(4-bromo-2-chloro-6-ethylphenyl)acetonitrile as a colorless oil (511mg, 72%). LC-MS B: t_(R)=0.99 min: no ionization.

A.2.60.4. 5-Bromo-1-chloro-2-(chloromethyl)-3-ethylbenzene

A cooled (0° C.) mixture of (4-bromo-2-chloro-6-ethylphenyl)methanol(645 mg, 2.58 mmol) and zinc chloride (9 mg, 0.064 mmol) in anh. DCM (10mL) is treated dropwise with thionyl chloride (0.37 mL, 5.17 mmol) andthe RM is stirred at 0° C. for 3 h, and then at RT overnight. The RM isconcentrated under reduced pressure affording crude5-bromo-1-chloro-2-(chloromethyl)-3-ethylbenzene as a grey oil (740 mg,quantitative). LC-MS B: t_(R)=1.09 min; no ionization.

A.2.60.5. (4-Bromo-2-chloro-6-ethylphenyl)methanol

To a cooled (−78° C.) solution of methyl4-bromo-2-chloro-6-ethylbenzoate (2.115 g, 7.62 mmol) in anh. THE (50mL) is added dropwise a solution of diisobutylaluminum hydride (1 M intoluene, 45.7 mL, 45.7 mmol). The mixture is further stirred at −78° C.,under nitrogen, for 15 min and is then allowed to warm-up to 0° C.Stirring at 0° C. is continued for 45 min, and the cooled RM is treatedsuccessively with water (2 mL), 2.8 N aq. NaOH (2 mL) and water (5 mL).The mixture is then allowed to warm-up to RT and is further stirred for30 min. The resulting mixture is filtered over celite, washing with THEand the filtrate is concentrated to dryness under reduced pressure.EtOAc and water are added and the layers are separated. The aqueouslayer is extracted twice with EtOAc and the combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords pure(4-bromo-2-chloro-6-ethylphenyl)methanol (645 mg, 34%). LC-MS B:t_(R)=0.89 min; no ionization.

A.2.60.6. Methyl 4-bromo-2-chloro-6-ethylbenzoate

To a solution of 4-bromo-2-chloro-6-ethylbenzoic acid (2.660 g, 10.10mmol) in anh. DMF (20 mL) at RT are added cesium carbonate (4.933 g,15.10 mmol) and iodomethane (0.76 mL, 12.10 mmol) and the RM is stirredat RT for 1.5 h. Water and Et₂O are added and the layers are separated.The aqueous layer is extracted twice with Et₂O and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords methyl 4-bromo-2-chloro-6-ethylbenzoate as acolorless oil (1.930 g, 69%). LC-MS B: t_(R)=1.03 min; no ionization.

A.2.60.7. 4-Bromo-2-chloro-6-ethylbenzoic acid

To a cooled (0° C.) solution of 4-bromo-2-chloro-6-fluorobenzoic acid(4.530 g, 17.00 mmol) in anh. THE (40 mL) is added dropwise a solutionof ethylmagnesium bromide (1.0 M in THF, 67.9 mL, 67.9 mmol) and the RMis further stirred at RT, under nitrogen, for 50 min. MeOH (20 mL) isthen added dropwise to the cooled (0° C.) reaction mixture that isfurther stirred at 0° C. for 5 min. The resulting mixture is thenconcentrated to dryness under reduced pressure and the residue ispartitioned between EtOAc and 2 M aq. HCl. The layers are separated, andthe aq. layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords 4-bromo-2-chloro-6-ethylbenzoic acid as acolorless solid (2.660 g, 59%). LC-MS B: t_(R)=0.86 min: no ionization.

A.2.61. Methyl2-(2-ethyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-ethyl-6-methylphenyl)acetate (1.176g, 4.34 mmol) in anh. DMF (15 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.112 g,4.34 mmol), potassium acetate (1.703 g, 17.30 mmol) and Pd(dppf)Cl₂ (353mg, 0.47 mmol). The RM is heated to 90° C., under nitrogen, for 16 h.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl2-(2-ethyl-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a light green oil (895 mg, 65%). LC-MS B: t_(R)=1.08 min;[M+H]⁺=319.28.

A.2.61.1. Methyl 2-(4-bromo-2-ethyl-6-methylphenyl)acetate

To a solution of 2-(4-bromo-2-ethyl-6-methylphenyl)acetic acid (2.993 g,11.60 mmol) in anh. DMF (20 mL) at RT are added cesium carbonate (7.585g, 23.30 mmol) and iodomethane (1.46 mL, 23.30 mmol) and the RM isstirred at RT, under nitrogen, for 5 h. Water and Et₂O are added and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=7/3) affords methyl2-(4-bromo-2-ethyl-6-methylphenyl)acetate as a yellow oil (1.176 g,37%). LC-MS B: t_(R)=1.03 min; no ionization.

A.2.61.2. 2-(4-Bromo-2-ethyl-6-methylphenyl)acetic acid

A mixture of 2-(4-bromo-2-ethyl-6-methylphenyl)acetonitrile (2.477 g,10.40 mmol), water (10 mL), 95% sulfuric acid (11 mL) and acetic acid(7.5 mL) is heated to 110° C., under nitrogen, for 1.5 h. The RM is thenallowed to cool to RT and is poured onto ice/water. The mixture isextracted twice with DCM and the combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure affording crude 2-(4-bromo-2-ethyl-6-methylphenyl)acetic acidas an off-white solid (2.993 g, quantitative). LC-MS B: t_(R)=0.81 min;no ionization.

A.2.61.3. 2-(4-Bromo-2-ethyl-6-methylphenyl)acetonitrile

A solution of 5-bromo-2-(chloromethyl)-1-ethyl-3-methylbenzene (2.849 g,11.50 mmol) in MeCN (30 mL) and water (3.7 mL) is treated with sodiumcyanide (764 mg, 15.00 mmol) and the RM is heated to 80° C., undernitrogen, for 1 h. The RM is then allowed to cool to RT and is dilutedwith water. Acetonitrile is removed under reduced pressure and the RM isextracted twice with DCM. The combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords2-(4-bromo-2-ethyl-6-methylphenyl)acetonitrile as a clear oil (2.477 g,90%). LC-MS B: t_(R)=0.99 min; no ionization.

A.2.61.4. 5-Bromo-2-(chloromethyl)-1-ethyl-3-methylbenzene

A cooled (0° C.) mixture of (4-bromo-2-ethyl-6-methylphenyl)methanol(2.525 g, 11.00 mmol) and zinc chloride (37.6 mg, 0.276 mmol) in anh.DCM (30 mL) is treated dropwise with thionyl chloride (1.61 mL, 22.00mmol) and the RM is stirred at 0° C. for 1 h. The RM is concentratedunder reduced pressure affording crude5-bromo-2-(chloromethyl)-1-ethyl-3-methylbenzene as a light brown oil(2.849 g, quantitative). LC-MS B: t_(R)=1.08 min; no ionization.

A.2.61.5. (4-Bromo-2-ethyl-6-methylphenyl)methanol

To a cooled (−78° C.) solution of methyl4-bromo-2-ethyl-6-methylbenzoate (3.355 g, 13.00 mmol) in anh.

THE (60 mL) is added dropwise a solution of diisobutylaluminum hydride(1 M in toluene, 39.0 mL, 39.0 mmol). The mixture is further stirred at−78° C., under nitrogen, for 15 min and is then allowed to warm-up to 0°C. Stirring at 0° C. is continued for 1 h, and the cooled RM is treatedsuccessively with water (1 mL), 2.8 N aq. NaOH (1 mL) and water (3 mL).The mixture is then allowed to warm-up to RT and is further stirred for30 min. The resulting mixture is filtered over celite, washing with THEand the filtrate is concentrated to dryness under reduced pressure.EtOAc and water are added and the layers are separated. The aqueouslayer is extracted twice with EtOAc and the combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords(4-bromo-2-ethyl-6-methylphenyl)methanol (2.525 g, 84%). LC-MS B:t_(R)=0.87 min; no ionization.

A.2.61.6. Methyl 4-bromo-2-ethyl-6-methylbenzoate

To a solution of 4-bromo-2-ethyl-6-methylbenzoic acid (3.465 g, 14.30mmol) in anh. DMF (35 mL) at RT are added cesium carbonate (9.288 g,28.50 mmol) and iodomethane (1.79 mL, 28.50 mmol) and the RM is stirredat RT for 1 h. Water and Et₂O are added and the layers are separated.The aqueous layer is extracted twice with Et₂O and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/1) affords methyl 4-bromo-2-ethyl-6-methylbenzoate as aclear oil (3.355 g, 92%). LC-MS B: t_(R)=1.02 min; no ionization.

A.2.61.7. 4-Bromo-2-ethyl-6-methylbenzoic acid

To a cooled (0° C.) solution of 4-bromo-2-fluoro-6-methylbenzoic acid(4.000 g, 16.30 mmol) in anh. THE (40 mL) is added dropwise a solutionof ethylmagnesium bromide (1.0 M in THF, 49.0 mL, 49.0 mmol) and the RMis further stirred at RT, under nitrogen, overnight. MeOH (15 mL) isthen added dropwise to the cooled (0° C.) reaction mixture that isfurther stirred at 0° C. for 5 min. The resulting mixture is thenconcentrated to dryness under reduced pressure and the residue ispartitioned between EtOAc and 2 M aq. HCl. The layers are separated, andthe aq. layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/1) affords 4-bromo-2-ethyl-6-methylbenzoic acid as acolorless solid (3.465 g, 87%). LC-MS B: t_(R)=0.86 min; no ionization.

A.2.62. Methyl2-(3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate

A mixture of methyl 2-(3-ethylthiophen-2-yl)acetate (1.340 g, 7.27mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(1.119 g, 4.36 mmol), bis(1,5-cyclooctadiene)diiridium(I) dichloride(50.4 mg, 0.0727 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (47.8 mg,0.175 mmol) in THE (35 mL) is degassed with a nitrogen stream and thenstirred at 80° C., under nitrogen, overnight. The RM is concentratedunder reduced pressure and the residue is purified by FC (from heptaneto heptane/EtOAc=4/1) to afford methyl2-(3-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetateas a pale yellow oil (1.781 g, 79%). LC-MS B: t_(R)=1.04 min;[M+H]⁺=311.22.

A.2.62.1. Methyl 2-(3-ethylthiophen-2-yl)acetate

To a solution of 2-(3-ethylthiophen-2-yl)acetic acid (1.248 g, 7.33mmol) in anh. DMF (20 mL) at RT are added cesium carbonate (3.581 g,11.00 mmol) and iodomethane (0.55 mL, 8.79 mmol) and the RM is stirredat RT, under nitrogen, for 40 min. Water and Et₂O are added and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords methyl2-(3-ethylthiophen-2-yl)acetate as a yellow oil (1.340 g, 99%). LC-MS B:t_(R)=0.87 min; [M+H]⁺=185.19.

A.2.62.2. 2-(3-Ethylthiophen-2-yl)acetic acid

To a mixture of 2-(3-ethylthiophen-2-yl)acetonitrile (1.150 g, 7.60mmol) in EtOH (6 mL) and water (6 mL) at RT is added potassium hydroxide(1.280 g, 22.80 mmol) and the RM is heated at reflux, under nitrogen,for 75 min. The RM is then allowed to cool to RT and ethanol is removedunder reduced pressure. The resulting mixture is treated with 1 M aq.HCl and is extracted twice with DCM. The combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressureaffording crude 2-(3-ethylthiophen-2-yl)acetic acid as a yellow oil(1.247 g, 96%). LC-MS B: t_(R)=0.72 min; [M+H]⁺=170.94.

A.2.62.3. 2-(3-Ethylthiophen-2-yl)acetonitrile

A solution of 2-(chloromethyl)-3-ethylthiophene (506 mg, 3.15 mmol) inanhydrous DMSO (20 mL) is treated with sodium cyanide (617 mg, 12.60mmol) and the RM is heated to 80° C., under nitrogen, for 40 min. The RMis then allowed to cool to RT and is diluted with water. The resultingmixture is extracted three times with EtOAc and the combined organiclayers are washed with brine, dried over anh. MgSO₄, filtered andconcentrated under reduced pressure. Purification by FC (from heptane toheptane/EtOAc=1/1) affords 2-(3-ethylthiophen-2-yl)acetonitrile as ayellow oil (360 mg, 76%). LC-MS B: t_(R)=0.83 min; no ionization.

A.2.62.4. 2-(Chloromethyl)-3-ethylthiophene

To a cooled (0° C.) solution of (3-ethylthiophen-2-yl)methanol (500 mg,3.52 mmol) in anh. DCM (18 mL) are added successively triethylamine(0.63 mL, 4.57 mmol) and 4-dimethylaminopyridine (43 mg, 0.35 mmol).Methanesulfonyl chloride (0.32 mL, 4.22 mmol) is then added dropwise andthe resulting mixture is stirred at RT, under nitrogen, for 1 h. The RMis then diluted with water, the layers are separated and the aqueouslayer is extracted twice with DCM. The combined organic layers are driedover anh. MgSO₄, filtered and concentrated under reduced pressureaffording crude 2-(chloromethyl)-3-ethylthiophene as a yellow oil (505mg, 90%). LC-MS B: t_(R)=0.86 min: no ionization.

A.2.62.5. (3-Ethylthiophen-2-yl)methanol

To a cooled (−78° C.) solution of methyl 3-ethylthiophene-2-carboxylate(2.270 g, 13.30 mmol) in anh. THE (80 mL) is added dropwise a solutionof diisobutylaluminum hydride (1 M in toluene, 40.0 mL, 40.0 mmol). Themixture is further stirred at −78° C., under nitrogen, for 10 min and isthen allowed to warm-up to 0° C. Stirring at 0° C. is continued for 30min, and the cooled RM is then treated successively with water (1.5 mL),15% aq. NaOH (1.5 mL) and water (4 mL). The mixture is allowed towarm-up to RT and is further stirred for 1 h. The resulting mixture isfiltered over celite, washing with THE. EtOAc and water are added andthe layers are separated. The aqueous layer is extracted twice withEtOAc and the combined organic layers are dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=1/1) affords(3-ethylthiophen-2-yl)methanol as a colorless oil (2.030 g,quantitative). LC-MS B: t_(R)=0.66 min; no ionization.

A.2.62.6. Methyl 3-ethylthiophene-2-carboxylate

To a solution of 3-ethylthiophene-2-carboxylic acid (3.130 g, 19.00mmol) in anh. DMF (20 mL) at RT are added successively cesium carbonate(9.303 g, 28.60 mmol) and iodomethane (1.44 mL, 22.80 mmol) and the RMis stirred at RT for 1.5 h. Water and Et₂O are added and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure affording methyl3-ethylthiophene-2-carboxylate as a yellow oil (3.340 g, quantitative).LC-MS B: t_(R)=0.89 min; [M+H]⁺=171.04.

A.2.63. Methyl2-(2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-chloro-6-methylphenyl)acetate(2.614 g, 9.42 mmol) in anh. DMF (25 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.416 g,9.42 mmol), potassium acetate (3.697 g, 37.70 mmol) and Pd(dppf)Cl₂ (766mg, 1.04 mmol). The RM is heated to 90° C., under nitrogen, overnight.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl2-(2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a light green oil (1.939 g, 63%). LC-MS B: t_(R)=1.08 min;[M+H]⁺=325.19.

A.2.63.1. Methyl 2-(4-bromo-2-chloro-6-methylphenyl)acetate

To a solution of 2-(4-bromo-2-chloro-6-methylphenyl)acetic acid (2.648g, 10.00 mmol) in anh. DMF (25 mL) at RT are added cesium carbonate(6.548 g, 20.10 mmol) and iodomethane (1.26 mL, 20.10 mmol) and the RMis stirred at RT, under nitrogen, for 1 h. Water and Et₂O are added andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=7/3) affords methyl2-(4-bromo-2-chloro-6-methylphenyl)acetate as a clear oil (2.614 g,94%). LC-MS B: t_(R)=1.00 min: no ionization.

A.2.63.2. 2-(4-Bromo-2-chloro-6-methylphenyl)acetic acid

A mixture of 2-(4-bromo-2-chloro-6-methylphenyl)acetonitrile (2.504 g,10.20 mmol), water (9 mL), 95% sulfuric acid (11 mL) and acetic acid (7mL) is heated to 110° C., under nitrogen, for 4 h. The RM is thenallowed to cool to RT and is poured onto ice/water. The mixture isextracted twice with DCM and the combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure affording crude 2-(4-bromo-2-chloro-6-methylphenyl)acetic acidas an off-white solid (2.648 g, 98%). LC-MS B: t_(R)=0.86 min; noionization.

A.2.63.3. 2-(4-Bromo-2-chloro-6-methylphenyl)acetonitrile

A solution of 5-bromo-1-chloro-2-(chloromethyl)-3-methylbenzene (2.752g, 10.80 mmol) in MeCN (30 mL) and water (4 mL) is treated with sodiumcyanide (719 mg, 14.10 mmol) and the RM is heated to 80° C., undernitrogen, for 1 h. The RM is then allowed to cool to RT and is dilutedwith water. Acetonitrile is removed under reduced pressure and themixture is extracted twice with DCM. The combined organic layers aredried over anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords2-(4-bromo-2-chloro-6-methylphenyl)acetonitrile as a colorless solid(2.504 g, 94%). LC-MS B: t_(R)=0.96 min; no ionization.

A.2.63.4. 5-Bromo-1-chloro-2-(chloromethyl)-3-methylbenzene

A cooled (0° C.) mixture of (4-bromo-2-chloro-6-methylphenyl)methanol(2.529 g, 10.70 mmol) and zinc chloride (36.6 mg, 0.268 mmol) in anh.DCM (30 mL) is treated dropwise with thionyl chloride (1.57 mL, 21.50mmol) and the RM is stirred at 0° C. for 4 h. The RM is concentratedunder reduced pressure affording crude5-bromo-1-chloro-2-(chloromethyl)-3-methylbenzene as a dark pink solid(2.752 g, quantitative). LC-MS B: t_(R)=1.05 min; no ionization.

A.2.63.5. (4-Bromo-2-chloro-6-methylphenyl)methanol

To a cooled (−78° C.) solution of methyl4-bromo-2-chloro-6-methylbenzoate (3.450 g, 12.60 mmol) in anh. THE (60mL) is added dropwise a solution of diisobutylaluminum hydride (1 M intoluene, 38.0 mL, 38.0 mmol). The mixture is further stirred at −78° C.,under nitrogen, for 30 min and is then allowed to warm-up to RT.Stirring at RT is continued for 1.5 h, and the cooled RM is then treatedsuccessively with water (1 mL), 2.8 N aq. NaOH (1 mL) and water (3 mL).The mixture is allowed to warm-up to RT and is further stirred for 30min. The resulting mixture is filtered over celite, washing with THE andthe filtrate is concentrated to dryness under reduced pressure. EtOAcand water are added and the layers are separated. The aqueous layer isextracted twice with EtOAc and the combined organic layers are driedover anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords pure(4-bromo-2-chloro-6-methylphenyl)methanol (2.529 g, 85%). LC-MS B:t_(R)=0.90 min; no ionization.

A.2.63.6. Methyl 4-bromo-2-chloro-6-methylbenzoate

To a solution of 4-bromo-2-chloro-6-methylbenzoic acid (3.500 g, 13.30mmol) in anh. DMF (35 mL) at RT are added successively cesium carbonate(8.685 g, 26.70 mmol) and iodomethane (1.68 mL, 26.70 mmol) and the RMis stirred at RT for 1 h. Water and Et₂O are added and the layers areseparated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=7/3) affords methyl4-bromo-2-chloro-6-methylbenzoate as a dark orange oil (3.450 g, 98%).LC-MS B: t_(R)=0.99 min; no ionization.

A.2.64. Methyl1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate

To a solution of methyl 4-bromo-1-ethyl-1H-pyrrole-2-carboxylate (1.567g, 6.75 mmol) in anh. DMF (15 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.715 g,6.75 mmol), potassium acetate (2.651 g, 27.00 mmol) and Pd(dppf)Cl₂ (494mg, 0.67 mmol). The RM is heated to 90° C., under nitrogen, overnight.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/1) affords methyl1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylateas a light yellow oil (841 mg, 45%). LC-MS B: t_(R)=0.96 min;[M+H]⁺=280.24.

A.2.64.1. Methyl 4-bromo-1-ethyl-1H-pyrrole-2-carboxylate

To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (1.500 g, 7.21mmol) in anh. DMF (15 mL) at RT are added potassium carbonate (1.494 g,10.80 mmol) and iodoethane (1.43 mL, 8.65 mmol) and the RM is stirred atRT, under nitrogen, for 2.5 h. Water and Et₂O are added and the layersare separated. The aqueous layer is extracted twice with Et₂O and thecombined organic layers are washed with brine, dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=7/3) affords methyl4-bromo-1-ethyl-1H-pyrrole-2-carboxylate as a clear oil (1.567 g, 94%).LC-MS B: t_(R)=0.94 min; no ionization.

A.2.65. Methyl1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate

To a solution of methyl 4-bromo-1-propyl-1H-pyrrole-2-carboxylate (1.721g, 6.99 mmol) in anh. DMF (15 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.776 g,6.99 mmol), potassium acetate (2.745 g, 28.00 mmol) and Pd(dppf)Cl₂ (512mg, 0.69 mmol). The RM is heated to 90° C., under nitrogen, overnight.The RM is then allowed to cool to RT and is filtered through a pad ofcelite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare then washed with brine, dried over MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=3/1) affords methyl1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylateas a yellow oil (1.036 g, 51%). LC-MS B: t_(R)=1.02 min; [M+H]⁺=294.33.

A.2.65.1. Methyl 4-bromo-1-propyl-1H-pyrrole-2-carboxylate

To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (1.500 g, 7.21mmol) in anh. DMF (15 mL) at RT are added potassium carbonate (1.494 g,10.80 mmol) and 1-iodopropane (0.84 mL, 8.65 mmol) and the RM is stirredat RT, under nitrogen, overnight. Water and Et₂O are added and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=7/3) affords methyl4-bromo-1-propyl-1H-pyrrole-2-carboxylate as a clear oil (1.721 g, 97%).LC-MS B: t_(R)=0.99 min; no ionization.

A.2.66.2-Ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoicacid

Ethyl2-ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(960 mg, 2.38 mmol) is dissolved in MeOH/THF (1:1) (10 mL). Then NaOH10% (4.77 mL, 11.9 mmol) is added and the RM is stirred at RT for 4 h.It is treated with HCl 2N (˜10 mL) to reach acidic pH (<2) and extractedwith EtOAc. The resulting organic phase is dried over MgSO₄ andconcentrated, yielding the title compound as a yellow solid (0.735 g,81%). LC-MS B: t_(R)=0.91 min; [M+H]⁺=311.26.

A.2.66.1. Ethyl2-ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

The title compound is prepared according to the procedure described forA.2.12., starting with ethyl 4-bromo-2-ethoxy-3-fluorobenzoate. LC-MS B:t_(R)=1.10 min; [M+H]⁺=339.26.

A.2.66.2. Ethyl 4-bromo-2-ethoxy-3-fluorobenzoate

To a solution for 4-bromo-3-fluoro-2-hydroxybenzoic acid (750 mg, 3.1mmol) and K₂CO (1070 mg, 7.74 mmol) in DMF (6 mL), is added ethyl iodide(0.508 mL, 6.35 mmol). The reaction is stirred for 2.5 d at RT, then itis partitioned between DCM and brine. The aqueous layer is re-extractedwith DCM, the combined organics are washed with brine then dried(MgSO₄), and concentrated under reduced pressure to afford the titlecompound as a dark orange oil. LC-MS B: t_(R)=1.03 min; [M+H]⁺=291.01.

A.2.67. Methyl3-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

To a solution of methyl 3-(4-bromo-2-methoxyphenyl)propanoate (0.899 g,3.26 mmol) in anh. DMF (10 mL) are added at RT4,4,4′,4,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.835 g,3.26 mmol), potassium acetate (1.278 g, 13.00 mmol) and Pd(dppf)Cl₂ (265mg, 0.35 mmol). The mixture is heated to 90° C., under nitrogen,overnight. The RM is allowed to cool to RT and is filtered through a padof celite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare washed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=4/1)affords methyl3-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoateas alight yellow oil (0.752 g, 72%). LC-MS B: t_(R)=1.02 min;[M+H]⁺=321.22.

A.2.67.1. Methyl 3-(4-bromo-2-methoxyphenyl)propanoate

To a solution of 3-(4-bromo-2-methoxyphenyl)propanoic acid (1.000 g,3.86 mmol) in anh. DMF (10 mL) at RT are added cesium carbonate (2.515g, 7.72 mmol) and iodomethane (0.485 mL, 7.72 mmol) and the mixture isstirred at RT, under nitrogen, for 1 h. Water and Et₂O are added and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=7/3) affords methyl3-(4-bromo-2-methoxyphenyl)propanoate as a clear oil (0.899 g, 85%).LC-MS B: t_(R)=0.96 min; no ionization.

A.2.68. Methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-carboxylate

To a solution of methyl 5-bromo-2,3-dihydrobenzofuran-2-carboxylate(1.513 g, 5.86 mmol) in anh. DMF (20 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.504 g,5.86 mmol), potassium acetate (2.301 g, 23.40 mmol) and Pd(dppf)Cl₂ (477mg, 0.64 mmol). The mixture is heated to 90° C., under nitrogen,overnight. The RM is allowed to cool to RT and is filtered through a padof celite, washing with Et₂O. The filtrate is washed with water and theaqueous layer is extracted twice with Et₂O. The combined organic layersare washed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=7/3)affords methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-carboxylateas a light yellow oil (1.168 g, 66%). LC-MS B: t_(R)=0.98 min;[M+H]⁺=305.22.

A.2.68.1. Methyl 5-bromo-2,3-dihydrobenzofuran-2-carboxylate

To a solution of 5-bromo-2,3-dihydrobenzofuran-2-carboxylic acid (1.500g, 5.86 mmol) in anh. DMF (20 mL) at RT are added cesium carbonate(2.388 g, 7.33 mmol) and iodomethane (0.547 mL, 8.79 mmol) and themixture is stirred at RT, under nitrogen, overnight. Water and Et₂O areadded and the layers are separated. The aqueous layer is extracted twicewith Et₂O and the combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressure toafford methyl 5-bromo-2,3-dihydrobenzofuran-2-carboxylate as a yellowoil (1.513 g, quantitative). LC-MS B: t_(R)=0.90 min; no ionization.

A.2.69. Methyl2-(3-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate

A mixture of methyl 2-(3-propylthiophen-2-yl)acetate (0.600 g, 3.03mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(0.470 g, 1.82 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer(21.5 mg, 0.0325 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (20 mg,0.074 mmol) in THE (15 mL) is degassed with a nitrogen stream andstirred at 80° C., under nitrogen, overnight. The RM is concentratedunder reduced pressure and the residue is purified by FC (from heptaneto heptane/EtOAc=7/3) to afford methyl2-(3-propyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetateas a clear oil (0.671 g, 68%). LC-MS B: t_(R)=1.07 min; [M+H]⁺=325.24.

A.2.69.1. Methyl 2-(3-propylthiophen-2-yl)acetate

A mixture of methyl 2-(3-bromothiophen-2-yl)acetate (1.655 g, 7.04mmol), potassium n-propyltrifluorborate (1.223 g, 7.74 mmol) and cesiumcarbonate (6.881 g, 21.10 mmol) in toluene (24 mL) and water (12 mL) isdegassed three times with nitrogen. Palladium(II) acetate (79 mg, 0.35mmol) and RuPhos (0.346 g, 0.70 mmol) are then added and the mixture isheated to 95° C., under nitrogen, overnight. The RM is allowed to coolto RT, water is added and the mixture is extracted three times withEtOAc. The combined organic layers are washed with brine, dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords methyl2-(3-propylthiophen-2-yl)acetate as a yellow oil (1.336 g, 96%). LC-MSB: t_(R)=0.94 min; [M+H]⁺=199.26.

A.2.69.2. Methyl 2-(3-bromothiophen-2-yl)acetate

To a solution of 2-(3-bromothiophen-2-yl)acetic acid (2.000 g, 9.05mmol) in anh. DMF (20 mL) at RT are added cesium carbonate (5.895 g,18.10 mmol) and iodomethane (1.14 mL, 18.10 mmol) and the mixture isstirred at RT, under nitrogen, for 1 h. Water and Et₂O are added and thelayers are separated. The aqueous layer is extracted twice with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=7/3) affords methyl2-(3-bromothiophen-2-yl)acetate as a yellow oil (2.183 g, quantitative).LC-MS B: t_(R)=0.86 min; no ionization.

A.2.70. Methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-(trifluoromethyl)phenyl)acetate(2.556 g, 8.60 mmol) in anh. DMF (30 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.207 g,8.60 mmol), potassium acetate (3.378 g, 34.40 mmol) and Pd(dppf)Cl₂(0.700 g, 0.94 mmol). The mixture is heated to 90° C., under nitrogen,overnight. The RM is allowed to cool to RT and is filtered through a padof celite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare washed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. Purification by FC (from heptane to heptane/EtOAc=3/1)affords methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenyl)acetateas a yellow oil (2.256 g, 76%). LC-MS B: t_(R)=1.07 min; no ionization.

A.2.70.1. Methyl 2-(4-bromo-2-(trifluoromethyl)phenyl)acetate

To a solution of 2-(4-bromo-2-(trifluoromethyl)phenyl)acetic acid (2.694g, 9.52 mmol) in anh. DMF (25 mL) at RT are added cesium carbonate(6.202 g, 19.00 mmol) and iodomethane (1.20 mL, 19.00 mmol) and themixture is stirred at RT, under nitrogen, for 1 h. Water and Et₂O areadded and the layers are separated. The aqueous layer is extracted twicewith Et₂O and the combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords methyl2-(4-bromo-2-(trifluoromethyl)phenyl)acetate as a light yellow oil(2.556 g, 90%). LC-MS B: t_(R)=0.98 min; no ionization.

A.2.70.2. 2-(4-Bromo-2-(trifluoromethyl)phenyl)acetic acid

A mixture of 2-(4-bromo-2-(trifluoromethyl)phenyl)acetonitrile (2.385 g,9.03 mmol), water (8.5 mL), 95% sulfuric acid (9.5 mL) and acetic acid(6.5 mL) is heated to 110° C., under nitrogen, overnight. The RM isallowed to cool to RT and is poured onto ice/water. The mixture isextracted three times with DCM and the combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure affording crude2-(4-bromo-2-(trifluoromethyl)phenyl)acetic acid as a light yellow solid(2.694 g, quantitative). LC-MS B: t_(R)=0.85 min: no ionization.

A.2.70.3. 2-(4-Bromo-2-(trifluoromethyl)phenyl)acetonitrile

A solution of 4-bromo-1-(chloromethyl)-2-(trifluoromethyl)benzene (2.707g, 9.81 mmol) in MeCN (32 mL) and water (4 mL) is treated with sodiumcyanide (0.651 g, 12.80 mmol) and the mixture is heated to 80° C., undernitrogen, overnight. The RM is allowed to cool to RT and is diluted withwater. Acetonitrile is removed under reduced pressure and the mixture isextracted twice with DCM. The combined organic layers are dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords2-(4-bromo-2-(trifluoromethyl)phenyl)acetonitrile as a light yellowsolid (2.385 g, 92%). LC-MS B: t_(R)=0.95 min; no ionization.

A.2.70.4. 4-Bromo-1-(chloromethyl)-2-(trifluoromethyl)benzene

A cooled (0° C.) mixture of (4-bromo-2-(trifluoromethyl)phenyl)methanol(2.500 g, 9.62 mmol) and zinc chloride (32.8 mg, 0.24 mmol) in anh. DCM(25 mL) is treated dropwise with thionyl chloride (1.40 mL, 19.20 mmol)and the mixture is stirred at 0° C. for 4 h, and then at RT overnight.The RM is concentrated under reduced pressure affording crude4-bromo-1-(chloromethyl)-2-(trifluoromethyl)benzene as a light yellowoil (2.707 g, quantitative). LC-MS B: t_(R)=1.03 min; no ionization.

A.2.71. Methyl2-(2-ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a solution of methyl 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetate(1.939 g, 6.66 mmol) in anh. DMF (20 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.708 g,6.66 mmol), potassium acetate (2.615 g, 26.60 mmol) and Pd(dppf)Cl₂(0.542 g, 0.73 mmol). The mixture is heated to 90° C., under nitrogen,overnight. The RM is allowed to cool to RT and is filtered through a padof celite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl2-(2-ethoxy-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetateas a dark green oil (1.254 g, 56%). LC-MS B: t_(R)=1.05 min;[M+H]⁺=339.23.

A.2.71.1. Methyl 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetate

To a solution of 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetic acid (2.186g, 7.28 mmol) in anh. DMF (20 mL) at RT are added cesium carbonate(3.213 g, 9.86 mmol) and iodomethane (0.738 mL, 11.80 mmol) and themixture is stirred at RT, under nitrogen, for 15 min. Water and Et₂O areadded and the layers are separated. The aqueous layer is extracted twicewith Et₂O and the combined organic layers are washed with brine, driedover anh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords methyl2-(4-bromo-2-ethoxy-3-fluorophenyl)acetate as a clear oil (1.939 g,91%). LC-MS B: t_(R)=0.99 min; [M+H]⁺=291.10.

A.2.71.2. 2-(4-Bromo-2-ethoxy-3-fluorophenyl)acetic acid

A mixture of 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetonitrile (1.879 g,7.28 mmol), water (7 mL), 95% sulfuric acid (8 mL) and acetic acid (9mL) is heated to 110° C. under nitrogen, for 1.5 h. The RM is thenallowed to cool to RT and is poured onto ice/water. The mixture isextracted twice with DCM and the combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure affording 2-(4-bromo-2-ethoxy-3-fluorophenyl)acetic acid as anoff-white solid (2.186 g, quantitative). LC-MS B: t_(R)=0.85 min; noionization.

A.2.71.3. 2-(4-Bromo-2-ethoxy-3-fluorophenyl)acetonitrile

A solution of 1-bromo-4-(chloromethyl)-3-ethoxy-2-fluorobenzene (2.124g, 7.94 mmol) in MeCN (24 mL) and water (3 mL) is treated with sodiumcyanide (0.527 g, 10.30 mmol) and the mixture is heated to 80° C., undernitrogen, overnight. The RM is allowed to cool to RT and is diluted withwater. Acetonitrile is removed under reduced pressure and the mixture isextracted twice with DCM. The combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=7/3) affords2-(4-bromo-2-ethoxy-3-fluorophenyl)acetonitrile as a colorless solid(1.879 g, 92%). LC-MS B: t_(R)=0.97 min; no ionization.

A.2.71.4. 1-Bromo-4-(chloromethyl)-3-ethoxy-2-fluorobenzene

A cooled (0° C.) mixture of (4-bromo-2-ethoxy-3-fluorophenyl)methanol(1.947 g, 7.82 mmol) and zinc chloride (26.6 mg, 0.19 mmol) in anh. DCM(25 mL) is treated dropwise with thionyl chloride (1.14 mL, 15.60 mmol)and the mixture is stirred at 0° C. for 2 h. The RM is concentratedunder reduced pressure affording1-bromo-4-(chloromethyl)-3-ethoxy-2-fluorobenzene as a clear oil (2.124g, quantitative). LC-MS B: t_(R)=1.06 min; no ionization.

A.2.71.5. (4-Bromo-2-ethoxy-3-fluorophenyl)methanol

To a cooled (−78° C.) solution of ethyl4-bromo-2-ethoxy-3-fluorobenzoate (2.920 g, 10.00 mmol) in anh. THE (30mL) is added dropwise a solution of diisobutylaluminum hydride (1 M intoluene, 30.1 mL, 30.1 mmol) and the mixture is further stirred at −78°C., under nitrogen, for 45 min. The RM is then allowed to warm-up to 0°C. and is treated successively with water and with 2.8 N aq. NaOH. EtOAcis added, the layers are separated and the aqueous layer is extractedtwice with EtOAc. The combined organic layers are dried over anh. MgSO₄,filtered and concentrated under reduced pressure. Purification by FC(from heptane to heptane/EtOAc=7/3) affords(4-bromo-2-ethoxy-3-fluorophenyl)methanol as a colorless solid (1.947 g,78%). LC-MS B: t_(R)=0.85 min; no ionization.

A.2.71.6. Ethyl 4-bromo-2-ethoxy-3-fluorobenzoate

To a solution of 4-bromo-3-fluoro-2-hydroxybenzoic acid (3.000 g, 12.80mmol) in anh. DMF (25 mL) at RT are added potassium carbonate (3.529 g,25.50 mmol) and iodoethane (2.05 mL, 25.50 mmol) and the mixture isstirred at 80° C., under nitrogen, overnight. Water and Et₂O are addedand the layers are separated. The aqueous layer is extracted twice withEt₂O and the combined organic layers are washed with brine, dried overanh. MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=3/1) affords ethyl4-bromo-2-ethoxy-3-fluorobenzoate as a yellow oil (2.920 g, 79%). LC-MSB: t_(R)=1.04 min: [M+H]⁺=291.09.

A.2.72. Methyl2-(3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetate

A mixture of methyl 2-(3-(difluoromethoxy)thiophen-2-yl)acetate (0.365g, 1.64 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.253 g,0.98 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (11 mg, 0.0164mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine (11 mg, 0.039 mmol) in THE(8 mL) is degassed with a nitrogen stream and stirred at 80° C., undernitrogen, overnight. The RM is concentrated under reduced pressure andthe residue is purified by FC (from heptane to heptane/EtOAc=4/1) toafford methyl2-(3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)acetateas a yellow oil (0.473 g, 83%). LC-MS B: t_(R)=1.02 min; [M+H]⁺=349.15.

A.2.72.1. Methyl 2-(3-(difluoromethoxy)thiophen-2-yl)acetate

To a solution of 2-(3-(difluoromethoxy)thiophen-2-yl)acetic acid (0.401g, 1.93 mmol) in anh. DMF (8 mL) at RT are added cesium carbonate (0.941g, 2.89 mmol) and iodomethane (0.145 mL, 2.31 mmol) and the mixture isstirred at RT, under nitrogen, for 30 min. Water and Et₂O are added andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=4/1) affords methyl2-(3-(difluoromethoxy)thiophen-2-yl)acetate as a pale yellow oil (0.364g, 85%). LC-MS B: t_(R)=0.83 min; no ionization.

A.2.72.2. 2-(3-(Difluoromethoxy)thiophen-2-yl)acetic acid

A mixture of 2-(3-(difluoromethoxy)thiophen-2-yl)acetonitrile (0.306 g,1.62 mmol), potassium hydroxide (0.272 g, 4.85 mmol) in EtOH (3 mL) andwater (3 mL) is heated to 110° C., under nitrogen, for 2.5 h. The RM isallowed to cool to RT and is concentrated under reduced pressure. 1 Maq. HCl and DCM are successively added, the layers are separated and theaqueous layer is extracted twice with DCM. The combined organic layersare washed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure affording2-(3-(difluoromethoxy)thiophen-2-yl)acetic acid as an orange oil (0.296g, 88%). LC-MS B: t_(R)=0.68 min; no ionization.

A.2.72.3. 2-(3-(Difluoromethoxy)thiophen-2-yl)acetonitrile

A solution of 2-(chloromethyl)-3-(difluoromethoxy)thiophene (0.426 g,2.14 mmol) in anhydrous DMSO (10.5 mL) is treated with sodium cyanide(0.217 g, 4.29 mmol) and the mixture is heated to 80° C., undernitrogen, for 75 min. The RM is allowed to cool to RT and is dilutedwith water. The resulting mixture is extracted three times with Et₂O andthe combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=4/1) affords2-(3-(difluoromethoxy)thiophen-2-yl)acetonitrile as a pale yellow oil(0.306 g, 75%). LC-MS B: t_(R)=0.78 min; no ionization.

A.2.72.4. 2-(Chloromethyl)-3-(difluoromethoxy)thiophene

A cooled (0° C.) mixture of (3-(difluoromethoxy)thiophen-2-yl)methanol(0.360 g, 2.00 mmol) and zinc chloride (7 mg, 0.049 mmol) in anh. DCM(20 mL) is treated dropwise with thionyl chloride (0.291 mL, 3.99 mmol)and the mixture is stirred at RT for 3 h. The mixture is cooled to 0°C., treated dropwise with thionyl chloride (0.291 mL, 3.99 mmol) andfurther stirred at RT for 1 h. The RM is concentrated under reducedpressure to afford 2-(chloromethyl)-3-(difluoromethoxy)thiophene as ablack oil (0.328 g, 83%). LC-MS B: t_(R)=0.82 min; no ionization.

A.2.72.5. (3-(Difluoromethoxy)thiophen-2-yl)methanol

To a cooled (−78° C.) solution of methyl3-(difluoromethoxy)thiophene-2-carboxylate (1.450 g, 6.97 mmol) in anh.THE (50 mL) is added dropwise a solution of diisobutylaluminum hydride(1 M in THF, 21.0 mL, 21.0 mmol). The mixture is further stirred at −78°C., under nitrogen, for 20 min and is then allowed to warm-up to 0° C.Stirring at 0° C. is continued for 20 min, and the RM is treatedsuccessively with water (1 mL), 2.8 N aq. NaOH (1 mL) and water (2 mL).The mixture is then allowed to warm-up to RT and stirred for 1 h. Theresulting mixture was filtered over celite washing with THE and thefiltrate was concentrated to dryness under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=1/1) affords(3-(difluoromethoxy)thiophen-2-yl)methanol as a pale yellow oil (1.075g, 86%). LC-MS B: t_(R)=0.63 min; no ionization.

A.2.72.6. Methyl 3-(difluoromethoxy)thiophene-2-carboxylate

To a solution of 3-(difluoromethoxy)thiophene-2-carboxylic acid (0.500g, 2.45 mmol) in anh. DMF (4 mL) at RT are added successively cesiumcarbonate (1.196 g, 3.67 mmol) and iodomethane (0.185 mL, 2.94 mmol) andthe mixture is stirred at RT for 40 min. Water and Et₂O are added andthe layers are separated. The aqueous layer is extracted twice with Et₂Oand the combined organic layers are washed with brine, dried over anh.MgSO₄, filtered and concentrated under reduced pressure. Purification byFC (from heptane to heptane/EtOAc=1/1) affords methyl3-(difluoromethoxy)thiophene-2-carboxylate as a colorless oil (0.495 g,97%). LC-MS B: t_(R)=0.81 min; no ionization.

A.2.73. Methyl2-cyclopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a solution of methyl 4-bromo-2-cyclopropoxybenzoate (0.991 g, 3.65mmol) in anh. 1,4-dioxane (20 mL) are added at RT4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.936 g,3.65 mmol), potassium acetate (1.432 g, 14.60 mmol) and Pd(dppf)Cl₂ (297mg, 0.40 mmol). The mixture is heated to 95° C., under nitrogen,overnight. The RM is allowed to cool to RT and is filtered through a padof celite, washing with EtOAc. The filtrate is washed with water and theaqueous layer is extracted twice with EtOAc. The combined organic layersare dried over MgSO₄, filtered and concentrated under reduced pressure.Purification by FC (from heptane to heptane/EtOAc=7/3) affords methyl2-cyclopropoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateas an amber oil (1.004 g, 87%). LC-MS B: t_(R)=1.03 min; [M+H]⁺=319.25.

A.2.73.1. Methyl 4-bromo-2-cyclopropoxybenzoate

A cooled (0° C.) solution of diethylzinc (1 M in hexanes, 14.5 mL, 14.5mmol) in anh. DCM (10 mL) is treated dropwise with trifluoroacetic acid(0.767 mL, 9.92 mmol) and the mixture is stirred at 0° C., undernitrogen, for 10 min. Diiodomethane (2.38 mL, 29.00 mmol) is addeddropwise to the cooled mixture and stirring at 0° C. is continued for 10min. A solution of methyl 4-bromo-2-(vinyloxy)benzoate (0.981 g, 3.82mmol) in anh. DCM (15 mL) is added dropwise and the resulting mixture isfurther stirred at 0° C. for 30 min, and then at RT overnight. The RM istreated with aq. sat. NH₄Cl and the layers are separated. The aqueouslayer is extracted twice with DCM and the combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=4/1) affords methyl 4-bromo-2-cyclopropoxybenzoate as aclear oil (0.991 g, 96%). LC-MS B: t_(R)=0.95 min; [M+H]⁺=271.11.

A.2.73.2. Methyl 4-bromo-2-(vinyloxy)benzoate

To a cooled (0° C.) solution of 4-bromo-2-(vinyloxy)benzoic acid (1.161g, 4.78 mmol) in anh. DMF (20 mL) are added cesium carbonate (2.023 g,6.21 mmol) and iodomethane (0.452 mL, 7.17 mmol) and the mixture isstirred at 0° C., under nitrogen, for 15 min and then at RT for 1 h.Water and EtOAc are added and the layers are separated. The aqueouslayer is extracted twice with EtOAc and the combined organic layers arewashed with brine, dried over anh. MgSO₄, filtered and concentratedunder reduced pressure. Purification by FC (from heptane toheptane/EtOAc=7/3) affords methyl 4-bromo-2-(vinyloxy)benzoate as ayellow oil (1.181 g, 96%). LC-MS B: t_(R)=0.93 min; [M+H]⁺=256.99.

A.2.73.3. 4-Bromo-2-(vinyloxy)benzoic acid

A cooled (0° C.) solution of methyl 4-bromo-2-(2-chloroethoxy)benzoate(5.440 g, 18.50 mmol) in anh. THE (50 mL) is treated portionwise withpotassium tert-butoxide (2.485 g, 22.10 mmol) and the resulting solutionis stirred at 0° C., under nitrogen, for 45 min and then at RT for 30min. Additional potassium tert-butoxide (1.037 g, 9.241 mmol) is thenadded portionwise to the cooled (0° C.) mixture and stirring at RT iscontinued for 4 h. Water and EtOAc are added and the layers areseparated. The aqueous layer is acidified with 1M aq. HCl and extractedthree times with EtOAc. The combined organic layers are washed withbrine, dried over anh. MgSO₄, filtered and concentrated under reducedpressure. Purification by FC (from heptane to heptane/EtOAc=3/1) affords4-bromo-2-(vinyloxy)benzoic acid as a light orange solid (1.161 g, 26%).LC-MS B: t_(R)=0.79 min; no ionization.

A.2.73.4. Methyl 4-bromo-2-(2-chloroethoxy)benzoate

To a solution of methyl 4-bromo-2-hydroxybenzoate (5.000 g, 21.00 mmol)in anh. DMF (30 mL) at RT are added cesium carbonate (10.363 g, 31.50mmol) and 2-chloroethyl p-toluenesulfonate (4.71 mL, 25.20 mmol) and themixture is heated to 65° C., under nitrogen, for 2 h. The RM is allowedto cool to RT, water and Et₂O are added, and the layers are separated.The aqueous layer is extracted three times with Et₂O and the combinedorganic layers are washed with brine, dried over anh. MgSO₄, filteredand concentrated under reduced pressure. Purification by FC (fromheptane to heptane/EtOAc=4/1) affords methyl4-bromo-2-(2-chloroethoxy)benzoate as a colorless solid (5.840 g, 95%).LC-MS B: t_(R)=0.96 min: [M+H]⁺=293.10.

B—Preparation of Examples General Procedure A: Suzuki Coupling withPd(PPh₃)₄

A mixture of the respective pyrimidine halide derivative (A3) (0.15mmol), the respective boronic acid derivative (A4) (0.18 mmol), andK₂CO₃ 2M (0.3 mL, 0.6 mmol) in ethanol (3 mL) is purged with argon,Pd(PPh₃)₄ (0.0075 mmol) is added, and the RM is heated at 90° C.overnight. Alternatively, the reaction can be performed in a MWapparatus, at 120° C. for 15-30 min. The RM is filtered through a 0.45um Glass MicroFiber filter, washed with EtOH/MeCN and DMF. The filtrateis purified either by preparative HPLC or FC. Alternatively, it isdiluted with water, if needed the pH is adjusted, and extracted withEtOAc (3×). The combined organic extracts are dried (MgSO₄) andconcentrated under reduced pressure. The residue is purified bypreparative HPLC or by FC.

General Procedure B: Suzuki Coupling with Pd(PPh₃)₄ Followed by EsterHydrolysis

A mixture of the respective pyrimidine halide derivative (A3) (0.15mmol), the respective boronic acid derivative (A4) (0.18 mmol), andK₂CO₃ 2M (0.3 mL, 0.6 mmol) in EtOH (3 mL) is purged with argon,Pd(PPh₃)₄ (0.0075 mmol) is added, and the RM is heated at 90° C.overnight. Alternatively, the reaction can be performed in a MWapparatus, at 120° C. for 15-30 min. NaOH (32% solution, 0.5 mL) isadded, and the RM is stirred at RT for 2-20 h or at 90° C. for 0. 5-20h. It is then filtered through a 0.45 um Glass MicroFiber filter, washedwith EtOH and water. The filtrate is either purified directly bypreparative HPLC or diluted with 1N HCl, and extracted 3× with EtOAc.The combined organic extracts are dried (MgSO₄) and concentrated underreduced pressure. The residue is purified by preparative HPLC or by FC.

General Procedure C: Suzuki Coupling with PdCl₂(Dppf) Followed by EsterHydrolysis

A mixture of the respective pyrimidine halide derivative (A3) (0.15mmol), the respective boronic acid derivative (A4) (0.18-0.3 mmol), andCs₂CO₃ (0.75 mmol) in THE (4 mL) and water (0.5 mL) is purged withargon, Pd(dppf)Cl₂-DCM (0.015 mmol) is added, and the RM is heated at80° C. overnight. NaOH (32% solution, 0.5 mL) is added, and the RM isstirred at 80° C. for 2 h. It is then filtered through a 0.45 um GlassMicroFiber filter, washed with EtOH and water. The filtrate is eitherpurified directly by preparative HPLC or diluted with 1N HCl, andextracted 3× with EtOAc. The combined organic extracts are dried (MgSO₄)and concentrated under reduced pressure. The residue is purified bypreparative HPLC or by FC.

General Procedure D: Phosphonium-Mediated SNAr

To a solution of 6-hydroxy-pyrimidine derivative (0.1 mmol) in DMF (1mL) and TEA (0.4 mmol) is added PyBOP (0.16 mmol). The solution isstirred at RT for 15 min-1 h, then the respective aryl-ethylamine (0.125mmol) is added and the RM is stirred at 80° C. overnight. The RM iscooled to RT and treated with a few drops of water and purified bypreparative HPLC. Alternatively, the RM is diluted with EtOAc and washedtwice with brine. The organic layer is dried over MgSO₄, filtered andconcentrated. The residue is purified by preparative HPLC or by FC ifneeded. Alternatively, a solution of 6-hydroxy-pyrimidine derivative(0.1 mmol) in DMF (1 mL) is treated with DBU (0.15 mmol) and BOP (0.13mmol). The solution is stirred at RT for 15 min-1 h, then the respectivearyl-ethylamine (0.125 mmol) is added, and the RM is stirred at 80° C.for 2-20 h. The RM is cooled to RT and treated with a few drops of waterand purified by preparative HPLC. Or the RM is diluted with EtOAc andwashed twice with brine. The organic layer is dried over MgSO₄, filteredand concentrated. The residue is purified by preparative HPLC or by FCif needed.

Compounds of Examples 1-337 listed in Table 4 below are prepared byapplying either one of the above-mentioned procedures A, B or C to thepyrimidine halide derivatives A.1.1-A.1.96. coupled with commerciallyavailable boronic acid derivatives or with boronic acid derivativesA.2.1.-A.2.34.

TABLE 4 Examples 1-337 MS Data t_(R) [min] m/z Ex. Compound (LC-MS) [M +H]⁺ 13-Ethoxy-5-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 464.3 thiophene-2-carboxylic acid (*1) 25-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.1 (D) 459.2 thiophene-2-carboxylic acid (*1) 33-Ethoxy-5-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 468 thiophene-2-carboxylic acid 43-Ethoxy-5-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 456.2 thiophene-2-carboxylic acid (*1) 55-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-1.0 (D) 426.1 carboxylic acid 65-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-0.9 (D) 453.4 ethoxy-thiophene-2-carboxylic acid (*1) 73-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.1 (D) 434 carboxylic acid 83-Ethoxy-5-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 454.4 thiophene-2-carboxylic acid 93-Ethoxy-5-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-1.1 (D) 450.1 2-carboxylic acid 105-[6-(2-Benzo[b]thiophen-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-1.0 (D) 426.4 carboxylic acid 113-Ethoxy-5-{6-[2-(1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.1 (D) 438.4 carboxylic acid 123-Ethoxy-5-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-1.0 (D) 440.4 2-carboxylic acid 133-Ethoxy-5-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.0 (D) 428.2 carboxylic acid 143-Ethoxy-5-{6-[2-(5-methoxy-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 456.1 thiophene-2-carboxylic acid 155-{6-[2-(2,3-Dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.0 (D) 428.2 thiophene-2-carboxylic acid (*1) 163-Ethoxy-5-{6-[2-(6-fluoro-1-methyl-1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 441.3 thiophene-2-carboxylic acid (*1) 173-Ethoxy-5-{6-[2-(1-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.1 (D) 444.3 carboxylic acid (*1) 184-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 452.2 methylsulfanyl-benzoic acid 195-{6-[2-(4-Chloro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.2 (D) 484.4 thiophene-2-carboxylic acid (*1) 203-Ethoxy-5-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 440.1 thiophene-2-carboxylic acid (*1) 213-Ethoxy-5-{6-[2-(8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-ethylamino]-0.9 (D) 472.1 pyrimidin-4-yl}-thiophene-2-carboxylic acid 223-Ethoxy-5-{6-[2-(8-methyl-quinolin-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-0.7 (D) 435 carboxylic acid (*1) 233-Ethoxy-5-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.2 (D) 464.2 carboxylic acid (*1) 243-Ethoxy-5-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic0.9 (D) 409.2 acid 252-Cyclobutoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-1.1 (D) 488.3 yl}-benzoic acid (*1) 263-Ethoxy-5-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.9 (D) 458.1 pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 275-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.0 (D) 451.2 thiophene-2-carboxylic acid (*1) 284-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoic1.0 (D) 426 acid 294-{6-[2-(1-Fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-1.0 (D) 464.1 methylsulfanyl-benzoic acid (*1) 303-Ethoxy-5-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-0.9 (D) 442.3 4-yl}-thiophene-2-carboxylic acid 313-Ethoxy-5-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.2 (D) 478.3 thiophene-2-carboxylic acid (*1) 323-Ethoxy-5-{6-[2-(1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic0.9 (D) 409 acid 335-{6-[2-(1-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-1.0 (D) 445.1 carboxylic acid (*1) 343-Ethoxy-5-{6-[2-(6-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 439.9 thiophene-2-carboxylic acid 353-Ethoxy-5-{6-[2-(8-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-0.9 (D) 446.2 yl}-thiophene-2-carboxylic acid (*1) 363-Ethoxy-5-[6-(2-naphthalen-2-yl-ethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic1.1 (D) 420.1 acid 37(2-Ethoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 476 phenyl)-acetic acid (*1) 385-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-benzofuran-2-carboxylic0.8 (D) 416.2 acid 393-Ethoxy-5-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-1.0 (D) 472 4-yl}-thiophene-2-carboxylic acid 403-Ethoxy-5-{6-[2-(3-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.1 (D) 434.3 carboxylic acid 415-{6-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-0.9 (D) 428.4 thiophene-2-carboxylic acid 423-Ethoxy-5-{6-[2-(1-methyl-1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.0 (D) 423 carboxylic acid 435-{6-[2-(5,7-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-0.9 (D) 457.2 carboxylic acid (*1) 443-Ethoxy-5-[6-(2-indan-5-yl-ethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylicacid 1.1 (D) 410.1 455-{6-[2-(3-Difluoromethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.1 (D) 486.3 thiophene-2-carboxylic acid (*1) 465-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic1.0 (D) 410 acid (*1) 473-Ethoxy-5-{6-[2-(3-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 440.1 thiophene-2-carboxylic acid 483-(2-Hydroxy-ethoxy)-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 450.1 thiophene-2-carboxylic acid (*1) 493-Ethoxy-5-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 444.2 thiophene-2-carboxylic acid 505-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic1.0 (D) 410.1 acid (*1) 515-{6-[2-(8-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-1.0 (D) 462.1 ethoxy-thiophene-2-carboxylic acid 524-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 455.1 methylsulfanyl-benzoic acid (*1) 53(2-Ethoxy-4-{6-[2-(6-ethoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 494 phenoxy)-acetic acid (*1) 544-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.9 (D) 453 benzoic acid (*1) 555-{6-[2-(4,5-Difluoro-7-methoxy-2-methyl-benzofuran-6-yl)-ethylamino]-pyrimidin-4-1.1 (D) 490.4 yl}-3-ethoxy-thiophene-2-carboxylic acid 565-[6-(2-Chroman-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic1.0 (D) 426.3 acid 573-(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-1.0 (D) 462 2-yl)-propionic acid 585-[6-(2-Chroman-7-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic1.0 (D) 426.2 acid 594-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-1.0 (D) 460.3 methylsulfanyl-benzoic acid (*1) 603-Ethoxy-5-{6-[2-(3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-1.2 (D) 454.1 pyrimidin-4-yl}-thiophene-2-carboxylic acid 61(2-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 472.4 phenyl)-acetic acid (*1) 625-{6-[2-(3-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-1.2 (D) 454.2 carboxylic acid 632-Cyclobutoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 476.4 benzoic acid (*1) 645-{6-[2-(6-Cyano-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-0.9 (D) 439.2 thiophene-2-carboxylic acid (*1) 653-Ethoxy-5-{6-[2-(1-methyl-1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.0 (D) 423.3 carboxylic acid 663-Ethoxy-5-{6-[2-(8-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.1 (D) 438.3 carboxylic acid (*1) 675-{6-[2-(2,3-Dihydro-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-0.9 (D) 412.3 thiophene-2-carboxylic acid 682-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 457.2002 benzoic acid (*1) 693-Ethoxy-5-{6-[2-(5-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-0.8 (D) 439.1 carboxylic acid (*1) 702-Cyclobutoxy-4-{6-[2-(7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.9 (D) 494.3 ethylamino]-pyrimidin-4-yl}-benzoic acid 715-{6-[2-(1-Amino-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-0.9 (D) 435.1 carboxylic acid 725-{6-[2-(7-Fluoro-1-methyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylamino]-pyrimidin-4-1.3 (D) 481.4 yl}-3-trifluoromethyl-thiophene-2-carboxylic acid 734-{6-[2-(3-Cyano-1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.9 (D) 457.3 benzoic acid (*1) 742-Fluoro-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-6-propyl-1.1 (D) 444.2 benzoic acid 753-Ethoxy-5-{6-[2-(1-vinyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.2 (D) 446.2 carboxylic acid (*1) 762-Isobutyl-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.1 (D) 440.4 acid 774-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-0.8 (D) 447.2 benzoic acid (*1) 783-Ethoxy-5-{6-[2-(7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-1.0 (D) 474 pyrimidin-4-yl}-thiophene-2-carboxylic acid 792-Cyclobutoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-1.1 (D) 484.2 4-yl}-benzoic acid (*1) 80(2-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 480 phenoxy)-acetic acid (*1) 816-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.7 (D) 448.2 benzofuran-2-carboxylic acid 82(4-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.8 (D) 459.3 phenyl)-acetic acid (*1) 832-Difluoromethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 450 benzoic acid 84(4-{6-[2-(3-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenoxy)-0.8 (D) 469.3 acetic acid (*1) 856-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-benzofuran-2-carboxylic0.76 (B) 416.16 acid 865-{6-[2-(5,8-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-0.9 (D) 457.2 carboxylic acid (*1) 875-{6-[2-(7-Chloro-8-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.0 (D) 469.4 thiophene-2-carboxylic acid (*1) 885-[6-(2-Benzothiazol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic0.8 (D) 427.4 acid (*1) 89(2-Ethoxy-4-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 502.4 phenoxy)-acetic acid (*1) 905-{6-[2-(1-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-1.2 (D) 454.2 carboxylic acid 915-[6-(2-Benzothiazol-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic0.8 (D) 426.08 acid (*1) 924-{6-[2-(3-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic0.9 (D) 439.1 acid (*1) 935-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.7 (D) 448 benzofuran-2-carboxylic acid 943-Ethoxy-5-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-6-yl)-ethylamino]-0.85 (A) 487.98 pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 953-Ethoxy-5-{6-[2-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-1.0 (D) 442.3 4-yl}-thiophene-2-carboxylic acid (*1) 965-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-2-methyl-pyrimidin-4-yl]-3-ethoxy-0.9 (D) 440.3 thiophene-2-carboxylic acid (*1) 974-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-0.7 (D) 449 methylsulfanyl-benzoic acid (*1) 983-Ethoxy-5-{6-[2-(7-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-0.8 (D) 439.1 carboxylic acid (*1) 99(2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-0.7 (D) 496 4-yl}-phenoxy)-acetic acid 1002-Cyclobutoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 460.3 benzoic acid 1012-Ethoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 461.1751 benzoic acid 102(2-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 478.3 phenoxy)-acetic acid 103(2-Ethoxy-4-{6-[2-(3-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.8 (D) 468.3 acetic acid 1043-Ethoxy-5-{6-[2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1.0 (D) 459.1 ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid1052-Ethoxy-4-{6-[2-(3-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.0 (D) 438 acid 1063-Ethoxy-5-{6-[2-(6-fluoro-isoquinolin-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-0.6 (D) 439.2 carboxylic acid (*1) 107(4-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-0.9 (D) 464.3 acetic acid (*1) 1085-{6-[2-(7-Fluoro-isoquinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-0.9 (D) 463.1 thiophene-2-carboxylic acid (*1) 1092-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 450.1 benzoic acid (*1) 1102-Ethylsulfanyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.8 (D) 468.1 pyrimidin-4-yl}-benzoic acid 1115-[6-(2-Benzo[1,3]dioxol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-0.9 (D) 414.2 carboxylic acid 112(2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.7 (D) 464.1 acetic acid 1134-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-0.8 (D) 473.3 cyclobutoxy-benzoic acid (*1) 1145-{6-[2-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-0.9 (D) 412.1 thiophene-2-carboxylic acid (*1) 115(4-{6-[2-(1-Fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 478.3 methylsulfanyl-phenyl)-acetic acid (*1) 1164-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-0.8 (D) 453.9 methylsulfanyl-benzoic acid 1175-{6-[2-(7-Chloro-8-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-0.9 (D) 473.1 thiophene-2-carboxylic acid (*1) 118(2-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 464.3 phenyl)-acetic acid (*1) 1195-{6-[2-(6-Difluoromethoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-3-1.0 (D) 480.2 ethoxy-thiophene-2-carboxylic acid 120(2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-1.1 (D) 482.3 pyrimidin-4-yl}-phenoxy)-acetic acid (*1) 121{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxyl-acetic0.8 (D) 450.3 acid 122(2-Ethoxy-4-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.8 (D) 474.1 acetic acid 123[2-(5,7-Difluoro-quinolin-6-yl)-ethyl]-(6-quinolin-6-yl-pyrimidin-4-yl)-amine0.7 (D) 414.1 1242-Cyclobutoxy-4-{6-[2-(5-methoxy-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 460.1 benzoic acid 1254-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoic1.0 (D) 446 acid 1262-Ethoxy-4-{6-[2-(6-ethoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 464.3 benzoic acid (*1) 1272-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-4-carboxylic1.0 (D) 423.3 acid 1284-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.8 (D) 445.2 benzoic acid (*1) 129(4-{6-[2-(3-Difluoromethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.8 (D) 510.3 phenoxy)-acetic acid (*1) 130(E)-3-(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.2 (D) 460.3 thiophen-2-yl)-acrylic acid 1312-Cyclobutoxy-4-{6-[2-(1-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 464.4 benzoic acid (*1) 1324-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoic0.9 (D) 422.1 acid 1335-{6-[2-(1,3-Dimethyl-1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-1.0 (D) 437.3 2-carboxylic acid 1343-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.8 (D) 472.4 propionic acid (*1) 1355-[6-(2-Benzo[d]isothiazol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-0.9 (D) 427.2 carboxylic acid (*1) 136(2-Ethoxy-4-{6-[2-(1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.8 (D) 462.4 acetic acid 1374-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-0.8 (D) 468.3 methylsulfanyl-benzoic acid 1384-{6-[2-(2,3-Dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 424.2 methylsulfanyl-benzoic acid (*1) 139(2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-0.8 (D) 448 acetic acid 140(2-Ethoxy-4-{6-[2-(1-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.8 (D) 467.1 acetic acid (*1) 1412-Ethoxy-4-{6-[2-(1-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.0 (D) 438.1 acid (*1) 142(2-Ethoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.7 (D) 452.3 acetic acid 143(2-Ethoxy-4-{6-[2-(3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-0.9 (D) 478.4 pyrimidin-4-yl}-phenoxy)-acetic acid 144{4-[6-(2-Benzo[b]thiophen-6-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxyl-acetic0.8 (D) 450.3 acid 145(2-Ethoxy-4-{6-[2-(7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.7 (D) 498.3 pyrimidin-4-yl}-phenoxy)-acetic acid 1465-[6-(2-Benzooxazol-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylic0.8 (D) 411.2 acid (*1) 1474-[6-(2-Benzo[b]thiophen-6-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoic1.0 (D) 446.3 acid 148(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-1.0 (D) 448 yl)-acetic acid (*1) 1495-{6-[2-(6-Chloro-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 460.1 3-ethoxy-thiophene-2-carboxylic acid (*1) 1502-Butoxy-6-fluoro-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.2 (D) 474.1 benzoic acid 1512-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic0.8 (D) 434.3 acid 1524-{6-[2-(5-Methoxy-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 452.2 methylsulfanyl-benzoic acid 1534-{6-[2-(5,7-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethylsulfanyl-benzoic0.8 (D) 467 acid 154{4-[6-(2-Chroman-7-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxyl-aceticacid 0.7 (D) 450.1 1554-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-benzoicacid 0.9 (D) 420.1 156{6-[3-Ethoxy-4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-[2-(1-methyl-naphthalen-2-1.0 (D) 452.3 yl)-ethyl]-amine 157(2-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 462.4 phenyl)-acetic acid 1582-Ethylsulfanyl-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 450.3 benzoic acid 159(2-Ethoxy-4-{6-[2-(5-methoxy-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.7 (D) 464.1 acetic acid 160(2-Ethoxy-4-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.9 (D) 488.4 acetic acid (*1) 1612-{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenyl}-0.8 (D) 448.3 propionic acid 1622-Ethoxy-4-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic0.9 (D) 444.1 acid 163(4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 474.3 methylsulfanyl-phenyl)-acetic acid (*1) 1645-{6-[2-(1,3-Dihydro-isobenzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.2 (D) 412.3 thiophene-2-carboxylic acid (*1) 1655-{6-[2-(6-Chloro-2,2-difluoro-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-3-1.1 (D) 484 ethoxy-thiophene-2-carboxylic acid (*1) 166(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.8 (D) 458.4 acetic acid 1674-[6-(2-Benzo[b]thiophen-6-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-benzoicacid 0.9 (D) 420.3 1682-Cyclobutoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.1 (D) 454.4 acid 1692-Butoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.1 (D) 456.4 acid 1702-Cyclobutoxy-4-{6-[2-(2,3-dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-1.0 (D) 448.3 yl}-benzoic acid (*1) 1712-Cyclobutoxy-4-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.1 (D) 484.4 acid (*1) 1722-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.0 (D) 428 acid 1733-Ethoxy-5-{6-[2-(7-methoxy-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylamino]-pyrimidin-0.7 (D) 454.1 4-yl}-thiophene-2-carboxylic acid (*1) 1742-Ethoxy-4-{6-[2-(4-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 462.3 benzoic acid (*1) 175(2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.7 (D) 466.3 pyrimidin-4-yl}-phenyl)-acetic acid 1764-[6-(2-Benzo[b]thiophen-6-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoic0.9 (D) 422.2 acid 1773-Ethoxy-5-{6-[2-(7-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-0.6 (D) 435.3 carboxylic acid (*1) 1785-{6-[2-(4-Chloro-7-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-0.9 (D) 469.1 thiophene-2-carboxylic acid (*1) 179(4-{6-[2-(7-Chloro-8-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.7 (D) 493.1 phenoxy)-acetic acid (*1) 1802-Cyclobutoxy-4-{6-[2-(3-difluoromethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-1.1 (D) 506.3 yl}-benzoic acid (*1) 181(4-{6-[2-(2,3-Dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.8 (D) 436.3 phenyl)-acetic acid (*1) 1822-Cyclobutoxy-4-{6-[2-(1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.1 (D) 458.3 acid 1834-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-benzoic1.0 (D) 442.2 acid 184(2-Ethoxy-4-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-0.7 (D) 466.3 4-yl}-phenoxy)-acetic acid 1854-[6-(2-Indan-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid 0.9 (D) 406.3 1864-{6-[2-(4-Chloro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-1.0 (D) 480.1 methylsulfanyl-benzoic acid (*1) 1872-Cyclobutoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.9 (D) 478.2 pyrimidin-4-yl}-benzoic acid (*1) 1882-Ethoxy-4-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.0 (D) 458.4 acid (*1) 189{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenyl}-0.8 (D) 434.1 acetic acid 1904-{6-[2-(6-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 436.3 methylsulfanyl-benzoic acid 191(4-{6-[2-(5,7-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenoxy)-0.7 (D) 481.3 acetic acid (*1) 192(2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-0.8 (D) 480.4 4-yl}-phenyl)-acetic acid 1934-{6-[2-(6-Methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-0.8 (D) 436.3 benzoic acid 194(2-Ethoxy-4-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid 0.7 (D) 433.2 195(2-Ethoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-0.8 (D) 436.3 acetic acid 1962-Cyclobutoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.9 (D) 492.4 pyrimidin-4-yl}-benzoic acid 197(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.7 (D) 468.3 2-methylsulfanyl-phenyl)-acetic acid (*1) 198{4-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxyl-aceticacid 0.7 (D) 434.1 (*1) 1996-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.74 (B) 448.16 benzofuran-3-carboxylic acid 2002-Cyclobutoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.0 (D) 448 acid 2012-(2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.7 (D) 496.4 pyrimidin-4-yl}-phenoxy)-propionic acid 2022-{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxyl-0.8 (D) 464 propionic acid 2034-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.7 (D) 447 2-ethoxy-benzoic acid (*1) 2044-{6-[2-(4-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 436.2 methylsulfanyl-benzoic acid (*1) 205(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 457.1 phenylamino)-acetic acid 2062-Cyclobutoxy-4-[6-(2-indan-5-yl-ethylamino)-pyrimidin-4-yl]-benzoicacid 1.0 (D) 430.3 207(2-Ethoxy-4-{6-[2-(1-methyl-1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-0.7 (D) 447 phenoxy)-acetic acid 2082-Cyclobutoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-1.0 (D) 474.4 4-yl}-benzoic acid 209(4-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.7 (D) 459.1 phenyl)-acetic acid (*1) 2103-Ethoxy-5-{6-[2-(7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-0.8 (D) 483 ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid 2114-{6-[2-(3-Difluoromethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-1.0 (D) 480 benzoic acid (*1) 2124-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.8 (D) 447.4 methylsulfanyl-benzoic acid (*1) 2132-Cyclobutoxy-4-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 464.3 benzoic acid 2142-(2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.8 (D) 480.3 pyrimidin-4-yl}-phenyl)-propionic acid 2154-{6-[2-(4,5-Difluoro-7-methoxy-2-methyl-benzofuran-6-yl)-ethylamino]-pyrimidin-4-1.0 (D) 484.3 yl}-2-ethoxy-benzoic acid 2164-{6-[2-(8-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 441.9 2-methylsulfanyl-benzoic acid 217(4-{6-[2-(6-Difluoromethoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-0.7 (D) 504.3 2-ethoxy-phenoxy)-acetic acid 2182-Ethoxy-4-{6-[2-(5-methoxy-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 450.3 benzoic acid 2192-Methylsulfanyl-4-[6-(2-naphthalen-2-yl-ethylamino)-pyrimidin-4-yl]-benzoicacid 0.9 (D) 416.3 2203-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-1.0 (D) 468 [1,2,4]oxadiazol-5(4H)-one [tautomeric form:3-(2-ethoxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-[1,2,4]oxadiazol-5-ol]2212-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 448.4 benzoic acid 2224-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethylsulfanyl-benzoic0.9 (D) 436.4 acid 2232-(2-Ethoxy-4-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic0.7 (D) 447 acid 224(4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.8 (D) 466 methylsulfanyl-phenyl)-acetic acid (*1) 225(2-Ethoxy-4-{6-[2-(1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid 0.6 (D) 433.3 226[2-(1H-Indol-6-yl)-ethyl]-[6-(1H-indol-5-yl)-pyrimidin-4-yl]-amine 0.6(D) 354.3 2272-Ethoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid 0.9 (D) 422.3 2282-Cyclobutoxy-4-{6-[2-(5,7-difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic0.9 (D) 477.3 acid (*1) 229{4-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxyl-aceticacid 0.7 (D) 434.4 (*1) 2304-{6-[2-(8-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 458.2 2-methylsulfanyl-benzoic acid 2312-Cyclobutoxy-4-{6-[2-(8-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.0 (D) 458.1 acid (*1) 232N-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-0.9 (D) 471 oxalamic acid 2332-(2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 478.1 phenoxy)-propionic acid 234 2-(2-Hydroxy-ethoxy)-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 444.3 benzoic acid (*1) 2352-Cyclobutoxy-4-{6-[2-(8-methyl-quinolin-7-yl)-ethylamino]-pyrimidin-4-yl}-benzoic0.7 (D) 455.3 acid (*1) 2362-(2-Ethoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-0.8 (D) 466 propionic acid 2374-[6-(2-Benzothiazol-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid 0.7 (D) 423.1 (*1) 2384-{6-[2-(6-Fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-0.9 (D) 424.2 benzoic acid 239(2-Ethoxy-4-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-0.68 (A) 468.05 phenoxy)-acetic acid 2402-Ethoxy-4-{6-[2-(3-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid 1.0 (D) 428.3 2414-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoicacid (*1) 0.9 (D) 430.3 2423-Ethoxy-5-{6-[2-(1-ethyl-1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-1.0 (D) 437.2 carboxylic acid 2434-{6-[2-(8-Fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-0.9 (D) 434.1 benzoic acid (*1) 2442-Cyclobutoxy-4-{6-[2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-0.8 (D) 448.3 yl}-benzoic acid 2452-(2-Ethoxy-4-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-1.0 (D) 516 2-methyl-propionic acid 2464-{6-[2-(8-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 482.3 2-cyclobutoxy-benzoic acid 247(4-{6-[2-(3-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenoxy)-0.9 (D) 478.1 acetic acid (*1) 2484-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid 0.8 (D) 406.2 2496-{6-[2-(1H-Indol-6-yl)-ethylamino]-pyrimidin-4-yl}-1-methyl-1,2-dihydro-0.6 (D) 385.3 indazol-3-one 2504-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid 0.8 (D) 406.2 2513-Ethoxy-5-{6-[2-(5-methoxy-1-methyl-1H-indazol-6-yl)-ethylamino]-pyrimidin-4-yl}-1.2 (D) 454.2 thiophene-2-carboxylic acid (*1) 2524-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoicacid (*1 ) 0.9 (D) 430.3 2534-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.8 (D) 445.3 ethoxy-benzoic acid (*1) 2542-Ethoxy-4-{6-[2-(6-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-0.9 (D) 434.1 yl}-benzoic acid 2554-{6-[2-(2,3-Dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 422.3 ethoxy-benzoic acid (*1) 256(2-Ethoxy-4-{6-[2-(5-methoxy-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 448 phenyl)-acetic acid 2574-[6-(2-Chroman-6-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid 0.8 (D) 422.1 258(2-Ethoxy-4-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.0 (D) 486 phenyl)-acetic acid (*1) 2592-Ethoxy-4-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid 0.7 (D) 403.3 2604-{6-[2-(1-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-1.0 (D) 448.2 benzoic acid 2612-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.8 (D) 466.4 pyrimidin-4-yl}-benzoic acid 2622-Cyclobutoxy-4-{6-[2-(4,5-difluoro-7-methoxy-2-methyl-benzofuran-6-yl)-1.2 (D) 528 ethylamino]-pyrimidin-4-yl}-6-fluoro-benzoic acid (*1) 2634-{6-[2-(7-Chloro-8-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-1.0 (D) 489.3 cyclobutoxy-benzoic acid (*1) 2642-Cyclobutoxy-4-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-1.2 (D) 498.4 4-yl}-benzoic acid 2654-[6-(2-Chroman-7-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoicacid 0.9 (D) 446 2664-[6-(2-Chroman-6-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoicacid 0.9 (D) 446.3 267[2-(1H-Indol-6-yl)-ethyl]-[6-(1H-indol-6-yl)-pyrimidin-4-yl]-amine 0.7(D) 354.3 2682-Cyclobutoxy-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]- 1.0(D) 460.4 pyrimidin-4-yl}-benzoic acid (*1) 2692-Ethoxy-4-{6-[2-(8-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 432.2 benzoic acid (*1) 270(4-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 466.3 methylsulfanyl-phenyl)-acetic acid (*1) 271(2-Ethoxy-4-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-0.7 (D) 417.3 acetic acid 272646-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-1H-indole-3-0.7 (D) 415.2 carboxylic acid 2734-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}- 0.9(D) 471.3 2-cyclobutoxy-benzoic acid (*1) 274(2-Ethoxy-4-{6-[2-(3-methylamino-naphthalen-2-yl)-ethylamino]-pyrimidin-0.8 (D) 472 4-yl}-phenoxy)-acetic acid (1) 2752-Ethylsulfanyl-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-0.9 (D) 438.3 yl}-benzoic acid 2764-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 406.2 benzoic acid 2774-{6-[2-(6-Methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.8 (D) 440 methylsulfanyl-benzoic acid 2782-Cyclobutoxy-4-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid 0.8 (D) 429.3 2794-{6-[2-(3-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-1.0 (D) 448.4 benzoic acid (*1) 2802-Cyclobutoxy-4-{6-[2-(2-fluoro-5-methoxy-benzofuran-6-yl)-ethylamino]-pyrimidin-4-1.0 (D) 478.3 yl}-benzoic acid 281 3-Hydroxy-4-(4-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-cyclobut-3-0.7 (D) 411.2 ene-1,2-dione 2822-Ethoxy-6-methoxy-4-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 474.3 benzoic acid (*1) 2833-(5-{6-[2-(7-Fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-methoxy-thiophen-2-0.6 (D) 453.3 yl)-oxetan-3-ol 2842-Ethoxy-4-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoic1.1 (D) 472.4 acid (*1) 2854-[6-(2-Chroman-7-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid 0.8 (D) 422.1 2862-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.8 (D) 452.3 pyrimidin-4-yl}-benzoic acid (*1) 2872-Cyclobutoxy-4-{6-[2-(1-methyl-1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic0.9 (D) 443.3 acid 2882-Cyclobutoxy-4-{6-[2-(7-methyl-2,3-2,3-benzo[1,4]dioxin-6-yl)-ethylamino]-0.9 (D) 462.1 pyrimidin-4-yl}-benzoic acid 289(2-Ethoxy-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 448 phenyl)-acetic acid (*1) 290(2-Ethoxy-4-{6-[2-(6-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 448 phenyl)-acetic acid 2914-[6-(2-Benzothiazol-5-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoicacid (*1) 0.8 (D) 447.3 2924-{6-[2-(8-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 438 2-methylsulfanyl-benzoic acid 2934-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-benzoicacid (*1) 0.8 (D) 404.3 2945-{6-[2-(1H-Indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic0.7 (D) 364.2 acid amide 2952-Cyclobutoxy-4-{6-[2-(2,3-dihydro-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 432.3 benzoic acid 2962-Ethoxy-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 434.3 benzoic acid (*1) 297(2-Ethoxy-4-{6-[2-(3-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 448.4 phenyl)-acetic acid 298(2-Ethoxy-4-{6-[2-(5-methoxy-1-methyl-1H-indazol-6-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 478.3 phenoxy)-acetic acid (*1) 299(2-Ethoxy-4-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-0.7 (D) 452.3 phenyl)-acetic acid 3002,6-Dimethoxy-4-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 460.2 benzoic acid (*1) 301(4-{6-[2-(7-Chloro-8-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.7 (D) 497.3 phenoxy)-acetic acid (*1) 3025-(4-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-0.9 (D) 424.3 [1,2,4]oxadiazol-3(2H)-one [tautomeric form:5-(4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-[1,2,4]oxadiazol-3-ol] 303{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-0.8 (D) 436.2 phenyl}-acetic acid (*1) 3044-{6-[2-(5,7-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic0.8 (D) 451.3 acid (*1) 305(4-{6-[2-(6-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.9 (D) 450.1 methylsulfanyl-phenyl)-acetic acid (*1) 3062-Cyclobutoxy-4-{6-[2-(3-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-1.0 (D) 460.1 yl}-benzoic acid 3072,6-Difluoro-4-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-phenol0.7 (D) 367.4 308{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-2-methyl-pyrimidin-4-yl]-2-0.8 (D) 448.3 ethoxy-phenyl}-acetic acid (*1) 3094-[6-(2-Chroman-7-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-benzoic acid0.8 (D) 420.3 3104-{6-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.7 (D) 424.3 2-methylsulfanyl-benzoic acid 311{4-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenyl}-aceticacid 0.7 (D) 418 3122-Ethoxy-4-{6-[2-(3-methylamino-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.9 (D) 443 benzoic acid (*1) 3132-(2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.8 (D) 510 pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid 314(2-Ethoxy-4-{6-[2-(8-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-0.8 (D) 446 acetic acid (*1) 3152-Ethoxy-4-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-0.8 (D) 438.3 yl}-benzoic acid 316(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-1.2 (D) 462.3 2-yl)-acetic acid methyl ester 3174-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-benzoicacid (*1) 0.8 (D) 404.3 318[2-(5,7-Difluoro-quinolin-6-yl)-ethyl]-(6-isoquinolin-6-yl-pyrimidin-4-yl)-amine0.6 (D) 414.1 3194-{6-[2-(1H-Indol-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic0.7 (D) 405 acid 3204-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2,6-dimethoxy-benzoicacid 0.8 (D) 436.1 3212-{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxy}-0.9 (D) 478.3 2-methyl-propionic acid 3222-Cyclobutoxy-4-{6-[2-(1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid 0.8 (D) 429.4 3236-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-0.6 (D) 447 yl}-1H-indole-3-carboxylic acid 3244-{6-[2-(8-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 456.4 2-ethoxy-benzoic acid 3254-{6-[2-(6-Difluoromethoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-0.8 (D) 474.3 2-ethoxy-benzoic acid 326(4-{6-[2-(4-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.8 (D) 450.4 methylsulfanyl-phenyl)-acetic acid (*1) 3272-Ethoxy-4-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-0.8 (D) 436 4-yl}-benzoic acid 3284-{6-[2-(1H-Indol-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid 0.7 (D) 405.3 3294-{6-[2-(7-Methoxy-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.6 (D) 450.2 2-methylsulfanyl-benzoic acid (*1) 330[2-(5,7-Difluoro-quinolin-6-yl)-ethyl]-[6-(1H-indol-5-yl)-pyrimidin-4-yl]-amine0.6 (D) 402.1 3312-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-6-1.0 (D) 423.3 carboxylic acid 332{4-[6-(2-Chroman-7-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenyl}-aceticacid 0.8 (D) 434.3 3332-Cyclobutoxy-4-{6-[2-(1,3-difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.1 (D) 476.1 benzoic acid (*1) 3344-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoic1.0 (D) 450.1 acid (*1) 3355-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.1 (D) 455.9 thiophene-2-carboxylic acid (*1) 3364-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-1.0 (D) 452.3 benzoic acid (*1) 3372-(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-0.7 (D) 434 4-yl}-phenyl)-acrylic acid

Example 338:3-{3-Ethoxy-5-[6-(2-quinolin-6-yl-ethylamino)-pyrimidin-4-y]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(3-ethoxy-5-(6-((2-(quinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-oland 2-(quinolin-6-yl) ethan-1-amine di-hydrochloride, the title compoundis obtained as a pale yellow solid. L-MS B: t_(R)=0.67 min;[M+H]⁺=461.07.

a)3-(3-Ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol

A suspension of3-(3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(5180mg, 12.1 mmol) in HCl(4M in dioxane, 100 mL) is heated at 10000overnight, cooled down to RT, and the solvent is partially removed. Thesolid residue is filtered off washing with water, and dried under highvacuum, affording the title compound as alight yellow solid. LC-MS B:t_(R)=0.66 min; [M+H]⁺=307.01.

b)3-(3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol

To a mixture of3-ethoxy-N′-hydroxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboximidamide(6930 mg, 22.6 mmol) and DBU (8.62 mL, 56.5 mmol) in Dioxane/DMSO (3:2,220 ml) is added CDI (5498 mg, 33.9 mmol). The RM is stirred at 100° C.for 30 min, then cooled to RT. Evaporation of the solvent andtrituration in 2N HCl affords the title compound as a yellow solid (7.15g, 99%). LC-MS A: t_(R)=0.89 min; [M+H]⁺=321.14.

c)3-Ethoxy-N′-hydroxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboximidamide

A suspension of3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile (6860 mg,24.7 mmol), TEA (10.3 mL, 74 mmol) and hydroxylamine hydrochloride (2.59mL, 61.7 mmol) in EtOH (220 mL) is refluxed for 3 h, then cooled to RTand treated with water (30 mL) The yellow solid is filtered off anddried under high vacuum. The filtrate is concentrated and the solid istriturated in water, filtered off and combined with the first crop. Thetitle compound is obtained as a yellow solid (6.93 g, 95%). LC-MS B:t_(R)=0.62 min; [M+H]⁺=295.23.

d) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile

Cyanuric chloride (6248 mg, 33.5 mmol) is added portionwise at 0° C. toa suspension of3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxamide (6940 mg,22.4 mmol) in DMF (130 mL). The RM is then stirred at RT for 45 min. Itis cooled at 0° C. and diluted with water. The solid is filtered off,washing with water and then EtOAc, and dried under high vacuum. Thefiltrate is extracted twice with EtOAc, combined organic layers arewashed with brine, dried over MgSO₄, filtered and concentrated underreduced pressure. Both solids are combined to afford the title compoundas a beige solid (5.49 g, 94%). LC-MS B: t_(R)=1.00 min; [M+H]⁺=262.26.

e) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxamide

CDI (4861 mg, 29.1 mmol) is added to a solution of3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylic acid (7410mg, 26.4 mmol) in THE (140 mL) at RT. The RM is stirred for 30 min, thenNH₄OH (25% solution, 61.1 mL, 397 mmol) is added, and the RM is stirredat RT for 30 min, then concentrated under reduced pressure, and theresidue is triturated in 2N HCl. The title compound is filtered off,dried under high vacuum, and obtained as a yellow solid (6.94 g, 94%).LC-MS B: t_(R)=0.79 min; [M+H]⁺=280.22.

f) 3-Ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylic acid

A suspension of methyl3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate (7870 mg,26.2 mmol) in MeOH (210 mL) and NaOH 2M (38.8 mL, 419 mmol) is stirredovernight at RT. It is then acidified with HCl 24.5% (8N) (60 mL), MeOHis removed under vacuum and the slurry is filtered, to afford the titlecompound as a yellow solid (7.41 g, 99%). LC-MS B: t_(R)=0.77 min;[M+H]⁺=281.19.

g) Methyl 3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carboxylate

A mixture of methyl3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroan-2-yl)thiophene-2-carboxylate(10520 mg, 30 mmol), 4-chloro-6-methoxypyrimidine (4645 mg, 31.5 mmol),Pd(dppf)Cl₂DCM (2449 mg, 3 mmol) and potassium phosphate tribasicmonohydrate (20719 mg, 90 mmol) in water (4 mL) and DMF (150 mL) isdegassed for 20 min under a nitrogen stream, then stirred at RT for 1h15. The RM is filtered through celite, the filtrate is concentratedunder vacuum, the residue is partitioned between water and EtOAc. Theorganic layer is further washed with brine, dried over MgSO₄, filteredand concentrated. Purification by FC (heptane/EtOAc, from 1:0 to 0:1)affords the title compound as a yellow solid (7.87 g, 89%). LC-MS B:t_(R)=0.93 min; [M+H]⁺=295.18.

h) Methyl3-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate

The title compound is prepared according to the synthesis of A.2.9.using methyl 3-ethoxythiophene-2-carboxylate, and obtained as a whitesolid; LC-MS B: t_(R)=0.63 min; [M+H]⁺=313.13.

Example 339:3-(3-Ethoxy-5-{6-[2-(1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(5-(6-((2-(1H-indol-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol](*2)

Following the general procedure D with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(Example 338-a) and 2-(1H-indol-5-yl)ethan-1-amine, the title compoundis obtained as a very pale yellow solid. LC-MS B: t_(R)=0.86 min;[M+H]⁺=449.04.

Example 340:3-{5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(5-(6-((2-(benzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure D with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(Example 338-a) and 2-(benzo[b]thiophen-5-yl)ethan-1-amine hydrochloride(A.1.26.1.), the title compound is obtained as a beige solid. LC-MS B:t_(R)=0.94 min; [M+H]⁺=465.72.

Example 341:3-(3-Ethoxy-5-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(3-ethoxy-5-(6-((2-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure D with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(Example 338-a) and2-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-amine(A.1.71.1.), the title compound is obtained as a beige solid. LC-MS B:t_(R)=0.90 min; [M+H]⁺=481.73.

Example 342:3-(3-Ethoxy-5-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(3-ethoxy-5-(6-((2-(6-methoxybenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure D with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(Example 338-a) and 2-(6-methoxybenzo[b]thiophen-5-yl)ethan-1-aminehydrochloride (A.1.31.1.), the title compound is obtained as a beigesolid. LC-MS B: t_(R)=0.96 min; [M+H]⁺=495.97.

Example 343:3-(3-Ethoxy-5-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(5-(6-((2-(1H-indol-6-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure D with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(Example 338-a) and 2-(1H-indol-6-yl)ethan-1-amine (A.1.41.1.), thetitle compound is obtained as an off-white solid. LC-MS B: t_(R)=0.86min: [M+H]⁺=449.08.

Example 344:3-{5-[6-(2-Benzo[1,3]dioxol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(5-(6-((2-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure D with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(Example 338-a) and 2-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine(A.1.80.1.), the title compound is obtained as a white solid. LC-MS B:t_(R)=0.88 min; [M+H]⁺=454.02.

Example 345:3-{3-Ethoxy-5-[6-(2-naphthalen-2-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(3-ethoxy-5-(6-((2-(naphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure D with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(Example 338-a) and 2-(naphthalen-2-yl)ethan-1-amine (A.1.5.1.), thetitle compound is obtained as a yellow solid. LC-MS B: t_(R)=0.97 min;[M+H]⁺=460.05.

Example 346:3-(5-{6-[2-(5,7-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(5-(6-((2-(5,7-difluoroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure D with3-(3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol(Example 338-a) and 2-(5,7-difluoroquinolin-6-yl)ethan-1-aminehydrochloride (A.1.55.1.), the title compound is obtained as a whitesolid. LC-MS B: t_(R)=0.90 min; [M+H]⁺=496.70.

Example347:3-Ethoxy-5-{6-[2-(7-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-N-hydroxy-thiophene-2-carboxamidine

A mixture of3-ethoxy-5-(6-((2-(7-fluoroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophene-2-carbonitrile(50 mg, 0.119 mmol), hydroxyamine hydrochloride (16.7 mg, 0.238 mmol)and NaHCO₃ (25 mg, 0.298 mmol) in water (0.026 mL) and EtOH (1.00 mL) isstirred in a sealed tube at 90° C. for 1.5 h. Once at RT, it is dilutedwith water and extracted with EtOAc. The organic layer is then washedtwice with brine, dried over MgSO₄, filtered and concentrated. Theresidue is purified by prep LC-MS to the title compound as a yellowsolid. (17.3 mg, 32%). LC-MS A: t_(R)=0.70 min; [M+H]⁺=479.02.

a)3-Ethoxy-5-(6-((2-(7-fluoroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophene-2-carbonitrile

Following the general procedure D with3-ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophene-2-carbonitrile and2-(7-fluoroquinolin-6-yl)ethan-1-amine hydrochloride (A.1.54.1.), thetitle compound is obtained as a beige solid. LC-MS A: t_(R)=0.78 min;[M+H]⁺=420.16.

b) 3-Ethoxy-5-(6-hydroxypyrimidin-4-yl)thiophene-2-carbonitrile

Following the procedure described for Example 338-a with3-ethoxy-5-(6-methoxypyrimidin-4-yl)thiophene-2-carbonitrile (Example338-d), the title compound is obtained as a white solid. LC-MS A:t_(R)=0.69 min; [M+H]⁺=289.01.

Example 348:3-(3-Ethoxy-5-{6-[2-(7-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(3-ethoxy-5-(6-((2-(7-fluoroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol]

Following the procedure described for Example 338-b with3-ethoxy-5-{6-[2-(7-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-N-hydroxy-thiophene-2-carboxamidine(Example 347), the title compound is obtained as a white solid. LC-MS A:t_(R)=0.70 min; [M+H]⁺=479.02.

Example 349:{6-[4-Ethoxy-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-pyrimidin-4-yl}-[2-(7-fluoro-quinolin-6-yl)-ethyl]-amine

To a suspension of3-ethoxy-5-(6-((2-(7-fluoroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophene-2-carbonitrile(Example 347-a, 35 mg, 0.0834 mmol) in toluene (0.63 mL) is addedtrimethylsilylazide (0.0173 mL, 0.125 mmol) and dibutyltin oxide (2.08mg, 0.00834 mmol). The RM is stirred at 110° C. for 16 h in a sealedtube, cooled to RT and partitioned between brine and EtOAc. The organicextracts are dried over MgSO₄, filtered and concentrated under reducedpressure. The residue is purified by prep. HPLC to afford the titlecompound as a white solid (6 mg, 15%). LC-MS A: t_(R)=0.66 min;[M+H]⁺=463.06.

Example 350:4-Ethoxy-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylicacid

To a solution of ethyl4-ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate (59 mg, 0.2mmol) in DMF (2 mL) are added TEA (0.14 mL, 1.0 mmol) and PyBop (156 mg,0.3 mmol). The RM is stirred at RT for a few minutes until completedissolution and 2-(1-methylnaphthalen-2-yl)ethan-1-amine hydrochloride(A.1.2.1., 56 mg, 0.25 mmol) is added. The RM is heated at 100° C. for30 min in the microwave apparatus. NaOH 10% (0.721 mL, 2 mmol) is addedand the RM is stirred at 70° C. overnight. Purification by prep. LC-MSaffords the title compound as a yellow solid. LC-MS B: t_(R)=0.97 min;[M+H]⁺=435.21.

a) Ethyl 4-ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate

Following the procedure described for the synthesis of Example 338-awith ethyl 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate,the title compound is obtained as a yellow solid. LC-MS B: t_(R)=0.78min; [M+H]⁺=296.15.

b) Ethyl 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate

To a solution of ethyl4-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate (1730 mg,6.15 mmol) in DMF (40 mL) at RT under argon is added K₂CO (2168 mg, 15.4mmol), and the RM is heated at 60° C. Iodoethane (0.749 mL, 9.23 mmol)is added and the RM is stirred at 75° C. overnight. It is then cooled toRT, and water (75 mL) is added. The aq layer is extracted with DCM, theorganic extracts are dried (MgSO₄), filtered and concentrated underreduced pressure, affording the crude title compound as an orange solid(1.75 g, 76%). LC-MS B: t_(R)=1.04 min; [M+H]⁺=310.24.

c) Ethyl 4-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate

To a solution of 6-methoxypyrimidine-4-carbothioamide (1000 mg, 5.85mmol) in toluene (40 mL) is added pyridine (1.9 mL, 23.4 mmol) at RT,followed by diethyl bromomalonate (1.52 mL, 8.19 mmol). The RM is heatedat reflux overnight, then cooled to RT and treated with HCl 2N. Theproduct is filtered off. The layers of the filtrate are separated andthe aq layer is extracted twice with EtOAC. The combined organic layersare dried over MgSO₄, filtered, evaporated to dryness. The residue iscombined with the first crop, yielding the title compound as a brownsolid (1.73 g, 99%). LC-MS B: t_(R)=0.89 min; [M+H]⁺=282.18.

Example 351:4-Ethyl-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylicacid

Following the procedure described for the synthesis of Example 350,using 2-(1-methylnaphthalen-2-yl)ethan-1-amine hydrochloride (A.1.2.1.)and ethyl 4-ethyl-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate, thetitle compound is obtained as a yellow solid. LC-MS B: t_(R)=0.97 min;[M+H]⁺=419.05.

a) Ethyl 4-ethyl-2-(6-hydroxypyrimidin-4-yl)thiazole-5-carboxylate

Following the procedure described for the synthesis of Example 350-awith ethyl 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate, thetitle compound is obtained as a beige solid. LC-MS B: t_(R)=0.73 min;[M+H]⁺=266.26.

b) Ethyl 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate

To a solution of methyl 2-chloro-3-oxovalerate (0.96 mL, 6.5 mmol) inEtOH (30 mL) is added 6-methoxypyrimidine-4-carbothioamide (1000 mg,5.91 mmol) and the mixture is refluxed overnight. Methyl2-chloro-3-oxovalerate (1.31 mL, 8.86 mmol) is added and the RM isfurther refluxed for 24 h, then cooled at RT and treated with water (15mL), cooled down to 0° C. The precipitate is filtered off, rinsed withMeOH and dried under high vacuum, affording the title compound as apinkish solid (485 mg, 28%). LC-MS B: t_(R)=1.07 min; [M+H]⁺=294.20.

Example 352:3-(4-Ethoxy-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(4-ethoxy-2-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol](*1)

Following the general procedure D with2-(1-methylnaphthalen-2-yl)ethan-1-amine hydrochloride (A.1.2.1.) and3-(4-ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol,the title compound is obtained as a yellow solid. LC-MS B: t_(R)=1.11min; [M+H]⁺=475.16.

a)3-(4-Ethoxy-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol

Following the procedure described for the synthesis of Example 338-awith3-(4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol,the title compound is obtained as a yellowish solid. LC-MS B: t_(R)=0.68min; [M+H]⁺=308.17.

b)3-(4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol

Following the procedure described for the synthesis of Example 338-bwith4-ethoxy-N′-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboximidamide,the title compound is obtained as a beige solid. LC-MS B: t_(R)=0.94min; [M+H]⁺=321.93.

c)4-Ethoxy-N′-hydroxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboximidamide

Following the procedure described for the synthesis of Example 338-cwith 4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbonitrile, thetitle compound is obtained as a deep yellow solid. LC-MS B: t_(R)=0.67min; [M+H]⁺=296.17.

d) 4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbonitrile

NH₄OH (25%, 4.05 mL, 26.3 mmol) and I₂ (1824 mg, 7.19 mmol) are added at0° C. to a solution of4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbaldehyde (465 mg,1.75 mmol) in THE (15 mL) and the RM is stirred at RT for 3 h. It isthen poured in 10 mL of NaHSO₃ 40% (15 mL) and extracted with EtOAc,dried over MgSO₄ and concentrated under vacuum, to afford the titlecompound as an orange solid. LC-MS B: t_(R)=1.02 min; [M+H]⁺=263.25.

e) 4-Ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carbaldehyde

A mixture of ethyl4-ethoxy-2-(6-methoxypyrimidin-4-yl)thiazole-5-carboxylate (Example350-b, 706 mg, 2.64 mmol) in THE (20 mL) is cooled down to −78° C. andDiBAl-H (1M in THF, 5.28 mL, 5.28 mmol) is added dropwise. The mixtureis stirred at RT overnight. The mixture is quenched at 0° C. by dropwiseaddition of water (200 uL), then NaOH 10% (400 uL) and finally water(600 uL). The aluminium precipitate is filtered over a pad of Celite andrinsed with EtOAc. The filtrate is dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue is dissolved in DCM (20mL) and MnO₂ (2701 mg, 26.4 mmol) is added. The mixture is stirred 5 hat RT, then filtered over a pad of Celite and rinsed with EtOAc. Thefiltrate is concentrated under reduced pressure, affording the titlecompound as a light orange solid. LC-MS B: t_(R)=0.97 min;[M+H]⁺=266.25.

Example 353:3-(4-Ethyl-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one[tautomeric form:3-(4-ethyl-2-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol]

Following the general procedure D, using3-(4-ethyl-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-oland 2-(1-methylnaphthalen-2-yl)ethan-1-amine hydrochloride (A.1.2.1.),the title compound is obtained as a yellow solid. LC-MS B: t_(R)=1.05min; [M+H]⁺=459.16.

a)3-(4-Ethyl-2-(6-hydroxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol

Following the procedure described for the synthesis of Example 338-awith3-(4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol,the title compound is obtained as a grey solid. LC-MS B: t_(R)=0.64 min;[M+H]⁺=292.17.

b)3-(4-Ethyl-2-(6-ethoxypyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol

Following the procedure described for the synthesis of Example 338-bwith4-ethyl-N′-hydroxy-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboximidamide,the title compound is obtained as a light orange solid. LC-MS B:t_(R)=0.92 min; [M+H]⁺=320.21.

c)4-Ethyl-N′-hydroxy-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboximidamide

Following the procedure described for the synthesis of Example 338-cwith 4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carbonitrile, thetitle compound is obtained as a light yellow solid. LC-MS B: t_(R)=0.66min; [M+H]⁺=294.21.

d) 4-Ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carbonitrile

Following the procedure described for the synthesis of Example 338-dwith 2-(6-ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxamide, the titlecompound is obtained as a beige solid. LC-MS B: t_(R)=1.04 min;[M+H]⁺=261.29.

e) 2-(6-Ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxamide

Following the procedure described for the synthesis of Example 338-ewith 2-(6-ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxylic acid, thetitle compound is obtained as an orange solid. LC-MS B: t_(R)=0.79 min;[M+H]⁺=279.25.

f) 2-(6-Ethoxypyrimidin-4-yl)-4-ethylthiazole-5-carboxylic acid

An ice-chilled solution of ethyl4-ethyl-2-(6-ethoxypyrimidin-4-yl)thiazole-5-carboxylate (Example 351-b,1000 mg, 3.09 mmol) in THF/MeOH 1:1 (15 mL) is treated with NaOH 10%(5.58 mL, 15.5 mmol) and stirred at RT for 20 h. The solvents areremoved under reduced pressure, the aqueous phase is extracted once withEt₂O. The aqueous phase is then acidified with 2N HCl and extracted withEtOAc (3×). The combined organic extracts are dried over MgSO₄, filteredand concentrated under reduced pressure, yielding the title compound asa greenish solid (522 mg, 64%). LC-MS B: t_(R)=0.88 min; [M+H]⁺=280.24.

Example 354:3-Ethoxy-5-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)-N-sulfamoylthiophene-2-carboxamide

3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid (Example 7, 50 mg, 0.15 mmol) is dissolved in DMSO/THF (2:1) (3.3mL) and CDI (28.1 mg, 0.173 mmol) is added. The RM is heated at 60° C.for 1 h, cooled to RT and treated with sulfamide (24.4 mg, 0.254 mmol)and DBU (0.0431 mL, 0.288 mmol). The RM is stirred at RT for 1 h. HCl 2M(5 mL) is added, the precipitate is filtered, then purified by prep HPLCto yield the title compound as a white solid (52 mg, 88%). LC-MS B:t_(R)=0.93 min; [M+H]⁺=512.13.

Example 355:N-(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbonyl)-methanesulfonamide

Following the procedure described for the synthesis of Example 354, with3-ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid (Example 7) and methanesulfonamide, the title compound is obtainedas a white solid. LC-MS B: t_(R)=1.06 min; [M+H]⁺=511.16.

Compounds of Examples 356-456 listed in Table 5 below are prepared byapplying either one of the above-mentioned procedures A, B or C to thepyrimidine halide derivatives A.1.1.-A.1.xx. coupled with commerciallyavailable boronic acid derivatives or with boronic acid derivativesA.2.1.-A.2.45.

TABLE 5 Examples 356-456 t_(R) [min] MS Data Ex. Compound (LC-MS C) m/z[M + H]⁺ 3565-{6-[2-(5,7-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-0.738 412.2 carboxylic acid amide 357(4-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.862 465.2 phenyl)-acetic acid (1*) 3584-{6-[2-(7-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.999 454.2 benzoic acid (1*) 3595-{6-[2-(7-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-1.147 460.2 thiophene-2-carboxylic acid 3604-{6-[2-(7-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-1.013 456.2 methylsulfanyl-benzoic acid 3612-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.944 436.1 benzoic acid 3623-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.091 442.1 thiophene-2-carboxylic acid (1*) 363(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.855 450.1 phenyl)-acetic acid (1*) 3644-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.954 438.1 methylsulfanyl-benzoic acid (1*) 3652-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.937 436.1 benzoic acid (1*) 3662-Cyclobutoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-1.039 462.1 yl}-benzoic acid (1*) 3673-Ethoxy-5-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.085 442 thiophene-2-carboxylic acid (1*) 368(2-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.845 450.1 phenyl)-acetic acid (1*) 3694-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.945 438.1 methylsulfanyl-benzoic acid (1*) 370{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-6-fluoro-0.941 450.2 phenyl}-acetic acid (1*) 371(2-Ethoxy-6-fluoro-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-0.957 480.1 pyrimidin-4-yl}-phenyl)-acetic acid (1*) 372(2-Ethoxy-6-fluoro-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-0.977 464.3 pyrimidin-4-yl}-phenyl)-acetic acid (1*) 373(2-Ethoxy-6-fluoro-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.826 482.2 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (1*) 374(2-Ethoxy-6-fluoro-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-1.03 488.4 pyrimidin-4-yl}-phenyl)-acetic acid (1*) 375(2-Ethoxy-6-fluoro-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-0.976 468.2 4-yl}-phenyl)-acetic acid (1*) 3763-Ethoxy-5-{6-[2-(7-methyl-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-1.114 438 thiophene-2-carboxylic acid (1*) 3774-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-0.977 446.4 benzoic acid (1*) 3784-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-0.997 434.1 benzoic acid (1*) 3794-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.842 448 2-propyl-benzoic acid (1*) 3804-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-1.049 454.1 propyl-benzoic acid (1*) 381(2-Methoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-0.797 448.1 yl}-phenyl)-acetic acid (1*) 382(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-0.797 436.2 phenyl)-acetic acid (1*) 383(2-Methoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-1.059 450.1 pyrimidin-4-yl}-phenyl)-acetic acid (1*) 384(2-Methoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-0.861 456.3 4-yl}-phenyl)-acetic acid (1*) 385(4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-0.885 460.1 phenyl)-acetic acid (1*) 386(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-0.89 448.1 phenyl)-acetic acid (1*) 387(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-0.777 462.2 yl}-2-propyl-phenyl)-acetic acid (1*) 388(4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-0.95 468.2 propyl-phenyl)-acetic acid (1*) 3894-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-0.996 434.1 benzoic acid 390(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-0.897 448.2 phenyl)-acetic acid (1*) 3913-Ethoxy-5-{6-[2-(7-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.12 438.2 thiophene-2-carboxylic acid (1*) 392(4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.894 476 propoxy-phenyl)-acetic acid (1*) 393(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-0.905 464.1 phenyl)-acetic acid (1*) 394(4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-0.958 484.2 propoxy-phenyl)-acetic acid (1*) 3952-Ethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.84 466.2 ethylamino]-pyrimidin-4-yl}-benzoic acid (1*) 3962-Cyclobutoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.934 490 ethylamino]-pyrimidin-4-yl}-benzoic acid (1*) 397(4-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.823 476.1 pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid (1*) 398(2-Ethoxy-6-fluoro-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-0.888 496.1 yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (1*) 399(2-Ethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.776 478.1 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (1*) 4004-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.845 466.2 pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid (1*) 401rac-2-(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.83 476.1 pyrimidin-4-yl]-2-propyl-phenyl)-propionic acid (1*) 402(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.831 476.2 2-propyl-phenyl)-acetic acid (1*) 403(2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.889 496.2 pyrimidin-4-yl}-6-fluoro-phenyl)-acetic acid (1*) 4042-Ethoxy-4-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-0.968 466 pyrimidin-4-yl}-benzoic acid (1*) 4054-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.976 468.2 methylsulfanyl-benzoic acid (1*) 406(2-Ethoxy-4-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-0.876 480.3 pyrimidin-4-yl}-phenyl)-acetic acid (1*) 4072-Cyclobutoxy-4-≡6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-1.064 492 pyrimidin-4-yl}-benzoic acid (1*) 408(4-{6-[2-(5-Fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.8 480.1 pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid (1*) 409(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-0.939 462 phenyl)-acetic acid (1*) 410(4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.968 492.1 2-isobutyl-phenyl)-acetic acid (1*) 411(2-Isobutyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.821 476.1 pyrimidin-4-yl}-phenyl)-acetic acid (1*) 412(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.88 490.2 2-isobutyl-phenyl)-acetic acid (1*) 4134-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-1.052 448.2 benzoic acid (1*) 4144-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-1.056 448.1 benzoic acid (1*) 4154-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-1.075 478 isobutyl-benzoic acid (1*) 4162-Isobutyl-4-}6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.899 462 pyrimidin-4-yl}-benzoic acid (1*) 4174-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.961 476 2-isobutyl-benzoic acid (1*) 4182-Ethoxy-4-{6-[2-(3-ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.07 472.3 benzoic acid (1*) 4194-{6-[2-(3-Ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-1.075 474.3 methylsulfanyl-benzoic acid (1*) 420(2-Ethoxy-4-{6-[2-(3-ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-0.969 486 yl}-phenyl)-acetic acid (1*) 4213-(2-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.812 480.1 phenoxy)-propionic acid (1*) 4223-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.821 480.1 phenoxy)-propionic acid (1*) 4233-(2-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-0.87 500.2 4-yl}-phenoxy)-propionic acid (1*) 424(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.885 464 isopropoxy-phenyl)-acetic acid (1*) 425(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.822 492.1 2-isopropoxy-phenyl)-acetic acid (1*) 426(2-Isopropoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.807 492.1 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (1*) 427(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.948 518.2 2-trifluoromethoxy-phenyl)-acetic acid (1*) 428(4-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.938 518 pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic acid (1*)4294-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.992 454.1 methylsulfanyl-benzoic acid (1*) 4304-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-1.086 478.1 cyclobutoxy-benzoic acid (1*) 431(4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-0.886 466.4 phenyl)-acetic acid (1*) 4322-Isopropoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.904 478.1 ethylamino]-pyrimidin-4-yl}-benzoic acid (1*) 4335-{6-[2-(7-Difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino}-0.987 492 pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylic acid (1*) 434(2-Methoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.734 464.1 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (1*) 4352-Ethoxy-4-{6-[2-(5-fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.812 468.1 ethylamino]-pyrimidin-4-yl}-benzoic acid (1*) 4362-Ethoxy-4-{6-[2-(3-ethoxy-1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1.075 476.3 benzoic acid (1*) 4373-(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.77 466.2 methoxy-phenoxy)-propionic acid (1*) 4383-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-0.781 466.1 methoxy-phenoxy)-propionic acid (1*) 4392-Ethoxy-4-{6-[2-(7-ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.739 447.4 pyrimidin-4-yl}-benzoic acid (1*) 440(4-{6-[2-(7-Ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-0.8 459 2-propyl-phenyl)-acetic acid (1*) 441(2-Difluoromethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-0.835 500.1 yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (1*) 442(2-Difluoromethoxy-4-{6-[2-(5-fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-0.816 504.1 yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (1*) 443(2-Difluoromethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-0.987 492.4 pyrimidin-4-yl}-phenyl)-acetic acid (1*) 444(2-Ethyl-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.772 462 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (1*) 445(2-Ethyl-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-0.893 454.2 yl}-phenyl)-acetic acid (1*) 4462-Ethyl-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-0.985 440.1 benzoic acid (1*) 4472-Cyclopropoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.861 476 pyrimidin-4-yl}-benzoic acid (1*) 4482-Cyclopropoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-1.001 468 pyrimidin-4-yl}-benzoic acid (1*) 4492-Cyclopropoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-0.952 448.2 yl}-benzoic acid (1*) 450(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-0.879 504 yl}-2-trifluoromethoxy-phenyl)-acetic acid (1*) 4513-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form:3-(2-ethoxy-4-{6-[2-(7- 1.024 478.2fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5-ol] 452{6-[3-Ethoxy-4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-[2-(7-fluoro-0.961 462.3 benzo[b]thiophen-5-yl)-ethyl]-amine 4534-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutoxy-1.084 466.1 benzoic acid (1*) 4542-Butoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.088 466.3 benzoic acid (1*) 4553-Ethyl-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.174 428.2 thiophene-2-carboxylic acid (1*) 456(3-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.015 458.2 thiophen-2-yl)-acetic acid (1*)

Example 457:4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzamide

To a solution of4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid (Example 389, 0.08 mmol), ammonium chloride (5.7 mg, 0.096 mmol),DIPEA (0.0438 mL, 0.256 mmol) in DMF (0.6 mL) is added a solution ofHATU (31.9 mg, 0.084 mmol) in DMF (0.2 mL). The RM is stirred for 3d atRT, then directly purified by prep LC-MS, affording the title compoundas a white solid (16 mg, 46%). LC-MS C: t_(R)=0.834 min; [M+H]⁺=435.0.

Following the procedure described for Example 457, with4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid (Example 389) or2-ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid(Example 361) and the corresponding commercially available amines,the following examples are synthesized:

t_(R) [min] MS Data Ex. Compound (LC-MS C) m/z [M + H]⁺ 4584-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4- 0.869449.3 yl}-N-methyl-2-propyl-benzamide 4594-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4- 0.885507.2 yl}-N-(2-hydroxy-2-methyl-propyl)-2-propyl-benzamide 4604-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4- 0.814479.1 yl}-N-(2-hydroxy-ethyl)-2-propyl-benzamide 4612-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.869437.1 pyrimidin-4-yl}benzamide 4622-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.91451.3 pyrimidin-4-yl}-N-methyl-benzamide 4632-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.92509.3 pyrimidin-4-yl}-N-(2-hydroxy-2-methyl-propylybenzamide 4642-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.844481.3 pyrimidin-4-yl}-N-(2-hydroxy-ethyl)-benzamide

Compounds of Examples 465-564 listed in Table 6 below are prepared byapplying either one of the above-mentioned procedures A, B or C to thepyrimidine halide derivatives A.1.1-A.1.xx. coupled with commerciallyavailable boronic acid derivatives or with boronic acid derivativesA.2.1.-A.2.xx.

TABLE 6 t_(R) [min] MS Data Ex. Compound (LC-MS C) m/z [M +H]⁺ 4652-Ethoxy-4-{6-[2-(3-methyl-benzo[b]thiophen-5-yl)-ethylamino]- 0.95434.3 pyrimidin-4-yl}-benzoic acid 466(2-Ethoxy-4-{6-[2-(3-methyl-benzo[b]thiophen-5-yl)-ethylamino]- 0.829464 pyrimidin-4-yl}-phenoxy)-acetic acid 4676-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]- 0.844 416.2benzofuran-3-carboxylic acid 4683-Hydroxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-1.303 420.3 4-yl}-thiophene-2-carboxylic acid methyl ester 469(2-Ethoxy-6-fluoro-4-{6-[2-(6-methyl-benzo[b]thiophen-5-yl)- 0.996 464.3ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 4702-Ethoxy-4-{6-[2-(7-methyl-benzo[b]thiophen-6-yl)-ethylamino]- 0.945432.2 pyrimidin-4-yl}-benzoic acid (*1) 4712-Cyclobutoxy-4-{6-[2-(7-methyl-benzo[b]thiophen-6-yl)-ethylamino]-1.051 457.9 pyrimidin-4-yl}-benzoic acid (*1) 472(2-Ethoxy-4-{6-[2-(7-methyl-benzo[b]thiophen-6-yl)-ethylamino]- 0.844446.2 pyrimidin-4-yl}-phenyl)-acetic acid (*1) 4734-{6-[2-(7-Methyl-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-0.95 434 2-methylsulfanyl-benzoic acid (*1) 474rac-5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2,3- 0.733416.1 dihydro-benzofuran-2-carboxylic acid (*1) 475(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.804 436.1 2-methoxy-phenyl)-acetic acid (*1) 4762-Ethoxy-4-{6-[2-(7-methyl-benzo[b]thiophen-5-yl)-ethylamino]- 0.95432.3 pyrimidin-4-yl}-benzoic acid (*1) 4774-{6-[2-(7-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.955 433.9 2-methylsulfanyl-benzoic acid (*1) 4784-{6-[2-(7-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.006 430.1 2-propyl-benzoic acid (*1) 479{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-propoxy-0.859 446.3 phenyl}-acetic acid (*1) 480(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.774 478.1 pyrimidin-4-yl}-2-propoxy-phenyl)-acetic acid (*1) 481rac-2-{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-0.905 444.3 propyl-phenyl}-propionic acid (*1) 482 rac-2-(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.935 462.2pyrimidin-4-yl}-2-propyl-phenyl)-propionic acid (*1) 4834-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]- 1.015464.1 pyrimidin-4-yl}-2-propyl-benzoic acid (*1) 4843-Ethoxy-5-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)- 1.116 472.1ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 485(4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]- 0.824466.1 pyrimidin-4-yl}-2-methoxy-phenyl)-acetic acid (*1) 486(4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]- 0.91478.2 pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid (*1) 487rac-2-(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.87 490ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-propionic acid (*1) 4883-Ethoxy-5-{6-[2-(7-trifluoromethyl-benzo[b]thiophen-5-yl)- 1.162 492.1ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylic acid (*1) 489(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.036 446.1 2-trifluoromethoxy-phenyl)-acetic acid (*1) 4904-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.975 452.1 2-ethoxy-benzoic acid (*1) 4914-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.01 450 2-isopropoxy-benzoic acid (*1) 4924-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.001 450 2-isopropoxy-benzoic acid (*1) 4932-Isopropoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.844 464.1 ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 4942-Cyclobutoxy-4-{6-[2-(7-difluoromethoxy-2,3-dihydro- 0.93 512.3benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 4954-{6-[2-(7-Difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.844488.2 ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoic acid (*1) 4964-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.87 392.1 benzoic acid (*1) 4974-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.869 422.1 2-methoxy-benzoic acid (*1) 498(4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.92 464.1 2-propyl-phenyl)-acetic acid (*1) 499(4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.081 506.3 2-trifluoromethoxy-phenyl)-acetic acid (*1) 500(4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-1.086 510.1 4-yl}-2-trifluoromethoxy-phenyl)-acetic acid (*1) 501(4-{6-[2-(3-Chloro-7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.945482.2 pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid (*1) 502(4-{6-[2-(3-Chloro-7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.9484.3 pyrimidin-4-yl}-2-ethoxy-phenyl)-acetic acid (*1) 503(4-{6-[2-(7-Ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]- 0.73446.2 pyrimidin-4-yl}-2-methoxy-phenyl)-acetic acid (*1) (LC-MS B) 504(4-{6-[2-(5-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]- 0.789446.1 pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid (*1) 505(2-Methoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.698434.1 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 506(2-Ethoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.743448.2 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 5073-(2-Methoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.678464 ethylamino]-pyrimidin-4-yl}-phenoxy)-propionic acid (*1) 5082-Ethoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.809 434ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 509(4-{6-[2-(5-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]- 0.91488.2 pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-acetic acid (*1) 510(2-Difluoromethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-0.844 500.1 yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 511(2-Difluoromethoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-0.809 470.1 yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 512(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]- 0.769462.1 pyrimidin-4-yl}-2-ethyl-phenyl)-acetic acid (*1) 513(2-Ethyl-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.734432.2 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 514(2-Ethyl-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.824434.1 pyrimidin-4-yl}-phenyl)-acetic acid (*1) 5152-Ethyl-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.804418.1 ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 5164-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]- 0.839448 pyrimidin-4-yl}-2-ethyl-benzoic acid (*1) 5172-Ethyl-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-0.955 410 yl}-benzoic acid (*1) 5182-Ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.93 420pyrimidin-4-yl}-benzoic acid (*1) 5192-Cyclopropoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.819 446.1 ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 5202-Cyclopropoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6- 0.784461.9 yl)-ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 5212-Cyclopropoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]- 0.98 438pyrimidin-4-yl}-benzoic acid (*1) 522(2-Difluoromethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-0.779 486.2 6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1)523 (2-Isopropoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-0.759 478 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 524(2-Ethyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)- 0.718448.2 ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 525(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.849 488.2 pyrimidin-4-yl}-2-trifluoromethyl-phenyl)-acetic acid (*1)526 (4-{6-[2-(7-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-0.784 446.2 pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid (*1) 527(4-{6-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-0.744 432.2 yl}-2-propyl-phenyl)-acetic acid (*1) 528(4-{6-[2-(7-Fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]- 0.784450.3 pyrimidin-4-yl}-2-propyl-phenyl)-acetic acid (*1) 5293-(4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4- 0.92434.2 yl)phenyl)-[1,2,4]oxadiazol-5(4H)-one [tautomeric form:3-(4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5-ol] 5307-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.774 434.3 1-methyl-3,4-dihydro-1H-quinazolin-2-one 5312-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.93 433 1H-indole-4-carboxylic acid (*1) 5324-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.794 394.3 2,6-dimethyl-phenol 5332-Ethylsulfanyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-1.006 454.1 pyrimidin-4-yl}-benzoic acid (*1) 5342-Cyclobutoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-1.041 464.3 pyrimidin-4-yl}-benzoic acid (*1) 5353-(3-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 1.187472.2 pyrimidin-4-yl}-thiophen-2-yl)-propionic acid (*1) 5363-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-0.908 446.1 yl}-phenyl)-4-hydroxy-cyclobut-3-ene-1,2-dione 537(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.915466.3 pyrimidin-4-yl}-phenyl)-oxo-acetic acid 5382-Cyclopropoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-1.086 464.3 pyrimidin-4-yl}-benzoic acid methyl ester 539[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethyl]-[6-(1H-indol-5-yl)- 0.779389.4 pyrimidin-4-yl]amine 540(2-Difluoromethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)- 0.935 474.3ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 541(2-Chloro-6-ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)- 0.991 470.1ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1) 542(2-Ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.854450.3 pyrimidin-4-yl}-6-methyl-phenyl)-acetic acid (*1) 5435-(4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-0.854 433.9 yl)phenyl)-[1,2,4]oxadiazol-3(2H)-one [tautomeric form:5-(4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-3-ol] 544(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.789 422.3 2-methyl-phenyl)-acetic acid (*1) 545(3-Ethyl-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.981442.4 pyrimidin-4-yl}-thiophen-2-yl)-acetic acid (*1) 546(2-Chloro-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.945456.2 pyrimidin-4-yl}-6-methyl-phenyl)-acetic acid (*1) 5471-Ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.749411.3 pyrimidin-4-yl}-1H-pyrrole-2-carboxylic acid (*1) 5484-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.794 425.1 1-propyl-1H-pyrrole-2-carboxylic acid (*1) 5496-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.89 434.1 benzofuran-3-carboxylic acid (*1) 5505-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 1.001477.3 pyrimidin-4-yl}-phenyl)-isoxazol-3-ol [tautomeric form:5-(2-ethoxy-4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)phenyl)isoxazol-3(2H)-one] 5512-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.981480.3 pyrimidin-4-yl}-6-propyl-benzoic acid (*1) 5522-Ethoxy-3-fluoro-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)- 0.99 456.3ethylamino]-pyrimidin-4-yl}-benzoic acid (*1) 5535-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-0.945 463.3 yl}-2-methoxy-phenyl)-isoxazol-3-ol [tautomeric form:5-(4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)-2-methoxyphenyl)isoxazol-3(2H)-one] 5542-Fluoro-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]- 0.965412.2 pyrimidin-4-yl}-benzoic acid (*1) 5554-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.874 408.3 2-methyl-benzoic acid (*1) 556(5-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.046 456.3 3-propyl-thiophen-2-yl)-acetic acid (*1) 5571-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-0.95 476.1 yl}-2-propyl-phenyl)-cyclopropanecarboxylic acid (*1) 5584-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.804 433.4 1H-indole-7-carboxylic acid (*1) 559(3-Difluoromethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)- 1.096 480.2ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-acetic acid (*1) 5603-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-0.829 452.1 yl}-2-methoxy-phenyl)-propionic acid (*1) 5612-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1.096 432.9 1H-indole-7-carboxylic acid (*1) 5626-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.779 434.3 1H-indazole-3-carboxylic acid (*1) 5634-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-0.91 410.2 2-hydroxy-benzoic acid (*1) 564(2-Ethoxy-3-fluoro-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)- 0.91 470ethylamino]-pyrimidin-4-yl}-phenyl)-acetic acid (*1)

Example 565:3-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazole-5(4H)-thione(tautomeric form:3-(2-ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazole-5-thiol)

To a solution of(E/Z)-2-ethoxy-N′-hydroxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)benzimidamide(79 mg, 0.166 mmol) in dioxane (0.8 ml) and DMSO (0.8 ml) are added1,1′-thiocarbonyldiimidazole (46.8 mg, 0.25 mmol) and DBU (0.0989 mL,0.649 mmol). The RM is heated at 9000 and stirred overnight. Dioxane isremoved under vacuo then the solution is filtered through a PTFE filter,washing with MeCN and DMF, and purified by prep. LC-MS, affording thetitle compound as a pale yellow powder (45 mg, 56%). LC-MS C:t_(R)=1.141 min; [M+H]⁺ 484.1.

a) (E/Z)-2-Ethoxy-N′-hydroxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)benzimidamide

A solution of2-ethoxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)benzonitrile(87 mg, 0.213 mmol), hydroxylamine hydrochloride (0.0224 mL, 0.532mmol), TEA (0.0745 mL, 0.532 mmol) and EtOH (2 ml) is heated at 9000 andstirred overnight. The RM is cooled to RT, and the precipitate iscollected by filtration, washed with water, EtOH and finally Et2O, anddried under high vacuum, yielding the title compound as a beige powder(79 mg, 84%). LC-MS B: t_(R)=0.68 min; [M+H]⁺=442.0.

b)2-Ethoxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)benzonitrile

Following the General Procedure A, with6-chloro-N-(2-(1-methylnaphthalen-2-yl)ethyl)pyrimidin-4-amine (A.1.2.)and 4-cyano-3-ethoxyphenylboronic acid, the title compound is obtainedas a white solid. LC-MS B: t_(R)=0.93 min; [M+H]⁺=408.97.

Example 566:3-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-[1,2,4]oxadiazol-5(4H)-one(tautomeric form:3-(2-ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-[1,2,4]oxadiazol-5-ol)

A MW vial is charged with(E/Z)-2-(2-ethoxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-N′-hydroxyacetimidamide(35 mg, 0.077 mmol), DBU (0.035 mL, 0.23 mmol) and1,1′-carbonyldiimidazole (26 mg, 0.154 mmol), dioxane (1 mL) and DMSO (1mL). The vial is capped and heated at 110° C. for 30 min in themicrowave apparatus. Once at RT the dioxane is removed and the mixtureis purified by prep LC-MS, affording the title compound as a white solid(23 mg, 62%). LC-MS C: t_(R)=0.91 min; [M+H]⁺=482.2.

a)(E/Z)-2-(2-Ethoxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-N′-hydroxyacetimidamide

2-(2-Ethoxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)acetonitrile(32 mg, 0.076 mmol) is dissolved in EtOH (1 mL) then hydroxylaminesolution (50% in H₂O, 0.023 mL, 0.379 mmol) is added. The mixture isheated at 120° C. for 30 min in the microwave apparatus, cooled to RT,and concentrated under reduced pressure, affording the title compound asa brown solid (35 mg, quant.). LC-MS B: t_(R)=0.68 min; [M+H]⁺=456.5.

b)2-(2-Ethoxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)acetonitrile

Following the General Procedure A, with6-chloro-N-(2-(1-methylnaphthalen-2-yl)ethyl)pyrimidin-4-amine (A.1.2.)and2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile,the title compound is obtained as a white solid. LC-MS B: t_(R)=0.90min; [M+H]⁺=423.4.

c)2-(2-ethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

The title compound is prepared according to the procedure described forA.2.12., starting with 2-(4-bromo-2-ethoxyphenyl)acetonitrile. LC-MS B:t_(R)=1.05 min; [M+H]⁺=288.4.

d) 2-(4-Bromo-2-ethoxyphenyl)acetonitrile

The title compound is prepared according to the procedure described forExample 338-d, starting with 2-(4-bromo-2-ethoxyphenyl)acetamide. LC-MSB: t_(R)=0.97 min: no ionization. ¹H NMR (400 MHz, d6-DMSO) δ: 7.22-7.42(m, 2H), 6.96-7.21 (m, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.78-3.86 (m, 2H),1.36 (m, 3H).

e) 2-(4-bromo-2-ethoxyphenyl)acetamide

The title compound is prepared according to the procedure described forExample 338-e, starting with 2-(4-bromo-2-ethoxyphenyl)acetic acid.LC-MS B: t_(R)=0.76 min; [M+H]⁺=257.85.

Example 567:3-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-[1,2,4]oxadiazole-5(4H)-thione(tautomeric form:3-(2-ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzyl)-[1,2,4]oxadiazole-5-thiol)

The title compound is prepared according to the procedure described forExample 566, using(E/Z)-2-(2-ethoxy-4-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-N′-hydroxyacetimidamide(Example 566-a) and 1,1′-thiocarbonyldiimidazole. LC-MS C: t_(R)=0.995min; [M+H]⁺=498.2.

II. Biological Assays

Compounds of the present invention may be further characterized withregard to their general pharmacokinetic and pharmacological propertiesusing conventional assays well known in the art such as angiogenesisassays or tumor growth inhibition assays, or for example relating totheir bioavailability in different species (such as rat or dog); or fortheir properties with regard to drug safety and/or toxicologicalproperties using conventional assays well known in the art, for examplerelating to cytochrome P450 enzyme inhibition and time dependentinhibition, pregnane X receptor (PXR) activation, glutathione binding,or phototoxic behavior.

EMT-6 Mouse Tumor Model

The EMT-6 cell line is established from a transplantable murine mammarycarcinoma that arose in a BALB/cCRGL mouse after implantation of ahyperplastic mammary alveolar nodule (Volence F J, et al, J Surg Oncol.1980, 13(1):39-44), obtained from ATCC (American Type culturecollection, Manassas, Virginia, USA).

EMT-6 tumour cells are grown as monolayer at 37° C. in a humidifiedatmosphere (5% CO2, 95% air) in RPMI 1640 containing 2 mM L glutaminesupplemented with 10% fetal bovine serum. For experimental use, tumourcells are detached from the culture flask with trypsin. The cells arecounted in a hemocytometer and their viability is assessed by trypanblue exclusion.

Tumours are induced in female BALB/c mice by either subcutaneousinjection of 1×10⁶ EMT-6 cells in 200 μL of RPMI 1640 into the rightflank or by injection of 2.5×10⁵ EMT-6 cells in 50 μL of RPMI1640 intothe mammary fat pad tissue. For the latter injection, female BALB/c miceare anaesthetized with Isoflurane and a 5 mm incision is made in theskin over the lateral thorax to expose the mammary fat pad tissue. Aftertumor cell injection the thoracic surface is gently dabbed with a 95%ethanol-dampened cotton-swab to kill tumor cells that may leak from theinjection site. The skin of mice is closed with 4-0 crinerce sutures.

Animals are monitored daily for behavior and survival and twice weeklyfor body weight and tumor growth. Tumor size is measured with calipersand tumor volume is calculated according to the following formula: Tumorvolume=(width²×length)/2.

When tumors reach between 60 and 100 mm³ (depending on the experiment),treatment with EP2 and/or EP4 antagonists is started and compound isgiven daily for at least 3 weeks.

Tumor weight is measured at the end of the study.

Biological In Vitro Assays

The antagonistic activities of the compounds of formula (I) on the EP2and EP4 receptors are determined in accordance with the followingexperimental method.

The assay is using the PathHunter™ HEK 293 PTGER2 and PTGER4 b-arrestincell lines from DiscoverX. The system is based on the Enzyme FragmentComplementation Technology. Two complementing fragments of theb-galactosidase enzyme are expressed within stably transfected cells.The larger portion of b-gal, termed EA for Enzyme Acceptor, is fused tothe C-terminus of b-arrestin 2. The smaller fragment, termed ProLink™tag, is fused to PTGER2 (EP2) or PTRGER4 (EP4) at the C-terminus. Uponactivation, b-arrestin is recruited which forces the interaction ofProLink and EA, allowing complementation of the two fragments of b-galand the formation of a functional enzyme which is capable of hydrolysingthe substrate and generating a chemiluminescent signal.

hEP2 b-Arrestin Assay:

The HEK 293 PTGER2 b-arrestin cells (DiscoverX 93-021-4C1) are detachedfrom culture dishes with a cell dissociation buffer (Invitrogen,13151-014), and collected in growing medium (GM: DMEM+Glutamax-I(Invitrogen 32430)/10% FCS, 1% Penicilin/streptomycin). 5000 cells perwell of a 384 well plate (white with white bottom Greiner 781080) areseeded in 20 ul per well of GM. Plate is incubated at 37° C., 5% CO2 for24 hours.

Stock solutions of test compounds are made at a concentration of 10 mMin DMSO, and serially diluted in DMSO to concentrations required forinhibition dose response curves (tested concentration range 10 μM-2 nMor 1 μM-0.2 nM).

PGE2 (Cayman 14010, stock solution: 10 mM in DMSO) is used as agonist at5 μM final concentration, corresponding to EC80.

Five microliters of diluted compounds are transferred into the assayplate. Plate is pre-incubated 15 minutes at 37° C. Then five microlitersof PGE2 (final conc. 5 μM) are transferred into the assay plate. Plateis incubated 120 minutes at 37° C.

PathHunter Glo Detection Kit components are thawed and mix according tomanufacturer's instructions: 1 part Galacton Star Substrate with 5 partsEmerald II™ Solution, and 19 parts of PathHunter Cell Assay Buffer,respectively. Twelve μl of reagent are transferred to the assay plateand incubate for 1 hour at RT in the dark. Luminescence counts are readon a BMG Fluostar Optima reader according to manufacturer'sinstructions.

For each compound concentration calculate of the percentage of activitycompared to DMSO control value as average ±STDEV. (each concentration ismeasured in duplicate)

IC₅₀ values and curves are generated with XLfit software (IDBS) usingDose-Response One Site model 203. When compounds were measured multipletimes, mean values are given.

hEP4 b-Arrestin Assay:

The HEK 293 PTGER4 b-arrestin cells (DiscoverX 93-030-4C1) are detachedfrom culture dishes with a cell dissociation buffer (Invitrogen,13151-014), and collected in growing medium (GM: DMEM+Glutamax-I(Invitrogen 32430)/10% FCS, 1% Penicilin/streptomycin). 5000 cells perwell of a 384 well plate (white with white bottom Greiner 781080) areseeded in 20 ul per well of GM. Plate is incubated at 37° C., 5% CO2 for24 hours.

Stock solutions of test compounds are made at a concentration of 10 mMin DMSO, and serially diluted in DMSO to concentrations required forinhibition dose response curves (tested concentration range 10 μM-2 nMor 1 μM-0.2 nM).

PGE2 (Cayman 14010, stock solution: 100 uM in DMSO) is used as agonistat 20 nM final concentration, corresponding to EC80.

Five microliters of diluted compounds are transferred into the assayplate. Plate is pre-incubated 15 minutes at 37° C. Then five microlitersof PGE2 (final conc. 20 nM) are transferred into the assay plate. Plateis incubated 120 minutes at 37° C.

PathHunter Glo Detection Kit components are thawed and mix according tomanufacturer's instructions: 1 part Galacton Star Substrate with 5 partsEmerald II™ Solution, and 19 parts of PathHunter Cell Assay Buffer,respectively. Twelve I of reagent are transferred to the assay plate andincubate for 1 hour at RT in the dark. Luminescence counts are read on aBMG Fluostar Optima reader according to manufacturer's instructions.

For each compound concentration calculate of the percentage of activitycompared to DMSO control value as average ±STDEV. (each concentration ismeasured in duplicate)

IC₅₀ values and curves are generated with XLfit software (IDBS) usingDose-Response One Site model 203. When compounds were measured multipletimes, mean values are given.

The antagonistic activities of the compounds of formula (I) on the EP2and EP4 receptors are also determined in accordance with the followingexperimental method.

Human tumor cell lines expressing endogenously either EP4 or EP2 areused and cAMP accumulation in cells upon PGE₂ stimulation is monitored.SF295 glioblastoma cells express high endogenous EP2 and no EP4, whereasBT549 breast cancer cells, express high endogenous EP4 levels and verylow EP2 levels.

As a detection method for cAMP the HTRF (homogeneous time resolvedfluorescence) Cisbio kit (HTRF cAMP dynamic 2 kit 20'000 tests CisbioCat. #62AM4PEC) was used, which is based on a competitive immunoassayusing a Cryptate-labeled anti-cAMP antibody and d2-labeled cAMP. NativecAMP produced by cells or unlabeled cAMP (for the standard curve)compete with exogenously added d2-labeled cAMP (acceptor) for binding tomonoclonal anti-cAMP-Eu3+Cryptate (donor). A FRET signal (FluorescenceResonance Energy Transfer) is obtained only if the labeled anti-cAMPantibody binds the d2 labelled cAMP, thus the specific signal (i.e.energy transfer) is inversely proportional to the concentration of cAMPin the standard or sample.

hEP2 cAMP Assay:

The SF295 cells (NCI/No. 0503170) are detached from culture dishes witha cell dissociation buffer (Invitrogen, 13151-014), and collected ingrowing medium (GM: RPMI1640 (Invitrogen 21875)/10% FCS, 1%Penicilin/streptomycin). Cells are counted washed and resuspended inassay buffer (AB; HBSS, 20 mM HEPES, 0.2% BSA; 2 mM IBMX). 4'000 cellsin 5 μl of AB are seeded per well of a small volume 384 well plate(black with flat bottom, Greiner 784076).

Stock solutions of test compounds are made at a concentration of 10 mMin DMSO, and serially diluted in DMSO to concentrations required forinhibition dose response curves (tested concentration range 30 μM-0.4nM; 30 μM-0.015 nM or 1 μM-0.01 nM).

PGE₂ (Cayman 14010, stock solution: 75 μM in DMSO) is used as agonist at75 nM final concentration, corresponding to EC80.

Two point five microliters of diluted compounds are transferred into theassay plate. Plate is pre-incubated 45 minutes at RT. Subsequently, 2.5microliters of PGE₂ (final conc. 75 nM) are transferred into the assayplate. Plate is incubated 30 minutes at RT. Five μl of each donor(anti-cAMP cryptate) and acceptor (cAMP-d2) are added and the plate isincubated another hour at RT in the dark and then read using a BMGLABTECH PHERAstar reader (Excitation: 337 nm, Emission: 620 and 665 nm).

The obtained Delta F (fluorescence) values (665 nm/620 nM) are convertedinto % cAMP values using the measurements of the cAMP calibratorprovided in the kit. For each compound concentration the percentage ofcAMP compared to DMSO control value as average ±STDEV (eachconcentration is measured in duplicate) is calculated.

IC₅₀ values and curves are generated with XLfit software (IDBS) usingDose-Response One Site model 203. When compounds were measured multipletimes, mean values are given.

hEP4 cAMP Assay:

The BT549 cells (NCI/No. 0507282) are detached from culture dishes witha cell dissociation buffer (Invitrogen, 13151-014), and collected ingrowing medium (GM: RPMI1640 (Invitrogen 21875)/10% FCS, 1%Penicilin/streptomycin). Cells are counted washed and resuspended inassay buffer (AB; HBSS, 20 mM HEPES, 0.2% BSA; 2 mM IBMX). 4'000 cellsin 5 μl of AB are seeded per well of a small volume 384 well plate(black with flat bottom, Greiner 784076).

Stock solutions of test compounds are made at a concentration of 10 mMin DMSO, and serially diluted in DMSO to concentrations required forinhibition dose response curves (tested concentration range 30 μM-0.4nM; 30 μM-0.015 nM or 1 μM-0.01 nM).

PGE₂ (Cayman 14010, stock solution: 6 μM in DMSO) is used as agonist at6 nM final concentration, corresponding to EC80.

Two point five microliters of diluted compounds are transferred into theassay plate. Plate is pre-incubated 45 minutes at RT. Subsequently, 2.5microliters of PGE₂ (final conc. 6 nM) are transferred into the assayplate. Plate is incubated 30 minutes at RT. Five μl of each donor(anti-cAMP cryptate) and acceptor (cAMP-d2) are added and the plate isincubated another hour at RT in the dark and then read using a BMGLABTECH PHERAstar reader (Excitation: 337 nm, Emission: 620 and 665 nm).

The obtained Delta F (fluorescence) values (665 nm/620 nM) are convertedinto % cAMP values using the measurements of the cAMP calibratorprovided in the kit. For each compound concentration the percentage ofcAMP compared to DMSO control value as average ±STDEV (eachconcentration is measured in duplicate) is calculated.

IC₅₀ values and curves are generated with XLfit software (IDBS) usingDose-Response One Site model 203. When compounds were measured multipletimes, mean values are given.

Antagonistic activities (IC₅₀ in nM) in the beta-arrestin and cAMPassays of exemplified compounds are displayed in Table 7:

TABLE 7 hEP2 hEP4 hEP2 b- hEP4 b- cAMP cAMP Ex arr IC₅₀ arr IC₅₀ IC₅₀IC₅₀ 1 6 2 8 1 2 113 3 79 1 3 1 26 2 4 11 4 2 3 5 39 5 28 3 6 11 6 37 47 21 14 12 5 8 5 22 1 6 9 59 6 67 6 10 237 21 145 6 11 13 277 7 12 7 203 7 13 12 9 15 8 14 23 22 55 8 15 177 12 28 8 16 5 269 8 17 108 8 171 918 6 70 4 10 19 16 249 11 20 27 74 11 12 21 58 912 12 22 20 395 13 23 153 19 14 24 72 18 52 15 25 96 16 98 22 26 19 22 19 16 27 75 16 19 17 28135 96 74 61 29 53 33 52 17 30 29 51 14 17 31 6 7740 18 32 199 56 161 1833 11 537 18 34 6 25 8 18 35 359 23 194 18 36 20 557 18 37 16 281 22 38226 123 210 28 39 4 14 2 19 40 126 25 228 20 41 405 30 164 21 42 240 25137 21 43 54 44 43 21 44 24 283 21 45 127 5 185 21 46 47 19 45 22 47 4585 91 22 48 66 22 49 10 223 8 23 50 61 27 52 24 51 230 22 207 25 52 31863 158 25 53 5 12 12 25 54 68 331 27 55 844 25 335 16 56 538 27 190 2857 195 34 191 28 58 13 9390 30 59 37 94 18 30 60 3 320 31 61 148 28 21446 62 16 301 32 63 16 50 12 33 64 25 41 28 33 65 33 304 35 66 21 1220 3567 123 40 110 36 68 65 70 46 49 69 438 59 222 38 70 209 441 38 71 24 30139 72 37 892 39 73 809 91 1770 39 74 450 257 151 40 75 86 483 41 76 360120 221 42 77 47 154 25 43 78 141 21 219 44 79 43 56 83 44 80 17 32 3745 81 122 1840 123 164 82 128 251 46 83 274 255 70 47 84 19 1280 47 8587 49 86 79 445 49 87 173 85 134 51 88 107 59 64 53 89 17 19400 54 90 26378 55 91 40 586 56 92 105 1680 57 93 275 1260 85 118 94 423 49 528 5995 25 447 59 96 148 92 57 61 97 192 147 78 63 98 33 314 64 99 16 60 1367 100 35 176 29 67 101 30 102 35 102 9 141 6 70 103 51 18 89 71 104 1291 13 71 105 40 53 76 73 106 135 831 74 107 950 76 108 66 740 77 109 34101 12 78 110 56 179 61 81 111 115 89 49 81 112 40 127 69 82 113 179 25182 114 222 640 222 85 115 243 53 682 85 116 76 135 23 86 117 53 131 6188 118 34 74 66 88 119 32 113 41 90 120 114 61 111 92 121 42 283 93 12219 324 95 123 353 588 97 124 113 215 95 99 125 116 226 129 99 126 8 66 6101 127 181 109 101 103 128 151 192 76 103 129 35 494 104 130 23 423 106131 68 353 106 132 82 161 66 107 133 42 482 109 134 63 358 84 135 198172 171 115 136 29 677 120 137 14 124 4 120 138 74 358 61 120 139 85 157131 121 140 95 459 121 141 131 328 122 142 121 180 177 127 143 22 787128 144 91 751 132 145 90 519 134 146 258 361 115 137 147 219 571 141148 174 46 126 141 149 194 619 144 150 230 222 219 144 151 32 618 35 145152 119 352 111 145 153 757 340 146 154 99 25000 147 155 232 301 161 151156 107 36 221 154 157 7 89 22 156 158 23 185 16 157 159 180 140 179 157160 35 24 93 158 161 199 524 130 162 134 371 158 163 85 98 246 158 164269 93 149 163 165 188 333 164 166 49 297 165 167 361 714 166 168 151128 214 168 169 141 269 125 168 170 241 124 94 168 171 83 62 120 181 172157 287 137 181 173 128 769 183 174 409 88 269 90 175 179 301 185 176179 293 185 177 156 280 186 178 30 164 54 188 179 309 568 188 180 55 692188 181 376 384 192 182 79 645 195 183 115 223 67 178 184 171 378 164200 185 258 452 200 186 194 811 202 187 74 144 64 206 188 45 105 142 206189 158 108 530 208 190 38 609 18 149 191 279 329 208 192 76 153 69 210193 10 349 12 211 194 325 295 212 195 245 373 217 196 21 199 37 217 197127 300 176 224 198 226 366 225 199 177 2160 62 138 200 57 510 108 227201 83 111 133 229 202 77 277 234 203 352 687 237 204 12 633 29 186 205118 47 190 244 206 304 572 248 207 234 673 248 208 8 130 5 248 209 832143 248 249 210 794 252 211 571 253 212 255 340 50 253 213 59 46 256 214216 674 258 215 1590 379 650 259 216 307 490 267 217 238 321 272 218 160651 405 278 219 202 486 129 220 113 141 283 221 8 2 285 222 279 287 223329 199 288 224 84 260 61 173 225 923 289 226 151 250 291 227 142 88 293228 392 194 300 229 483 304 230 831 508 311 231 286 5650 315 232 382 321233 29 76 322 234 113 325 235 772 325 236 121 147 327 237 388 908 160335 238 55 75 343 239 134 222 346 240 598 816 346 241 168 193 351 242495 443 351 243 493 147 2100 355 244 552 356 245 304 358 246 534 364 247797 365 248 132 270 50 366 249 196 171 368 250 112 609 77 287 251 105132 369 252 212 186 373 253 521 671 158 373 254 45 864 70 379 255 788272 380 256 296 381 257 417 282 389 258 3610 390 259 302 394 260 880 404261 53 396 20 406 262 1300 186 855 424 263 524 425 264 11800 425 26511400 428 266 444 537 428 267 306 431 268 25 688 47 342 269 1640 5886510 434 270 1520 404 5660 435 271 638 439 272 679 458 295 273 289 221140 455 274 1180 462 275 67 102 468 276 79 1820 47 474 277 51 437 14 324278 281 187 477 279 743 559 489 280 514 491 281 524 494 282 296 498 283618 502 284 125 >28100 509 285 341 7520 513 286 198 86 515 287 515 520288 156 85 523 289 144 964 358 525 290 163 438 194 527 291 815 269 538292 1510 688 538 293 255 540 294 786 561 295 603 520 568 296 34 1600 61583 297 2120 782 592 298 716 613 299 307 367 250 444 300 312 624 301 425626 302 384 520 303 313 384 746 633 304 408 652 305 57 1350 232 653 306610 274 654 307 677 658 308 866 926 674 309 >27700 677 310 937 564 683311 310 538 685 312 556 2490 689 313 273 691 314 3460 378 9230 701 315134 73 703 316 792 729 317 501 233 751 318 408 247 753 319 1180 354 559320 440 766 321 562 772 322 809 814 323 438 1900 114 835 324 899 858 325441 332 887 326 126 1070 160 910 327 296 159 920 328 287 919 108 938 329798 755 956 330 158 249 1040 331 69 135 1180 332 415 12200 1510 333 359128 334 791 408 1630 230 335 100 12 268 3 336 225 113 337 664 1320 13101430 338 15 459 64 339 66 10 90 22 340 12 3 104 11 341 12 14 41 36 342 73 20 19 343 9 2 23 12 344 33 39 33 14 345 6 683 30 346 57 282 110 347 31495 172 348 172 2 113 8 349 109 4 103 14 350 83 21 51 10 351 475 79 236167 352 42 5 142 24 353 237 9 115 109 354 41 32 27 56 355 55 29 46 95356 2340 828 357 22 967 17 358 538 138 219 90 359 40 9 61 2 360 137 69183 44 361 187 116 270 68 362 20 6 21 1 363 479 59 534 35 364 151 52 3718 365 77 149 29 55 366 84 119 30 47 367 7 2 6 1 368 221 66 119 37 36966 91 9 31 370 438 105 312 81 371 86 88 48 68 372 75 195 111 200 373 257118 286 117 374 334 52 304 45 375 229 46 294 66 376 50 13 188 11 377 868 27 92 378 20 36 110 66 379 51 155 87 245 380 16 17 124 54 381 51 126165 119 382 160 81 675 222 383 177 194 650 270 384 145 28 577 59 385 3071 180 134 386 64 28 453 54 387 61 49 205 62 388 45 13 626 51 389 51 25231 57 390 264 29 590 32 391 131 19 243 6 392 66 292 156 111 393 155 166439 81 394 163 80 639 70 395 4 98 5 128 396 2 44 1 20 397 7 35 25 34 3989 26 30 18 399 10 30 40 48 400 2 44 2 37 401 331 114 739 236 402 22 6148 131 403 57 65 135 112 404 20 80 27 71 405 9 79 7 18 406 45 62 220 101407 22 66 21 44 408 29 24 126 20 409 260 57 486 87 410 153 113 665 170411 97 31 325 94 412 20 40 57 79 413 62 41 119 38 414 219 48 505 88 41563 52 106 57 416 245 82 123 83 417 38 174 31 240 418 10 54 45 148 419 330 29 85 420 27 30 257 119 421 84 22 247 27 422 249 23 492 18 423 49 10230 6 424 424 80 782 89 425 65 152 226 356 426 9 46 22 48 427 17 90 17190 428 7 41 7 50 429 52 60 66 38 430 69 66 185 40 431 179 52 460 43 43220 87 10 72 433 30 19 57 13 434 26 58 25 95 435 46 110 28 80 436 16 31110 57 437 104 41 227 37 438 519 49 708 29 439 17 197 33 139 440 11 5125 65 441 10 53 21 31 442 82 27 224 81 443 107 29 549 43 444 15 43 22 80445 88 38 525 104 446 32 108 160 98 447 2 130 16 136 448 15 46 55 26 44983 46 131 21 450 66 97 165 80 451 71 21 660 16 452 103 21 371 18 453 10270 281 118 454 88 212 608 225 455 271 18 250 38 456 129 21 311 14 457200 176 458 550 104 459 683 236 460 207 161 461 231 121 462 325 197 463934 223 464 300 87 465 313 827 245 1400 466 206 171 190 1210 467 417 187155 468 564 571 469 502 480 470 343 420 471 207 300 472 680 246 473 137275 474 272 914 475 663 62 114 476 428 264 477 316 210 478 788 242 479345 158 480 170 207 481 328 63 329 482 444 91 323 483 26 115 484 3 3 485125 122 486 95 136 487 59 136 488 723 45 489 231 128 490 90 144 491 372148 492 204 142 493 642 497 494 340 209 495 77 193 496 588 908 497 449443 498 163 107 499 180 169 500 88 99 501 196 808 502 103 903 503 102157 504 108 167 505 427 929 506 172 332 507 170 209 508 85 748 509 29356 510 45 194 511 304 423 512 67 220 513 158 347 514 262 112 515 67 893516 23 930 517 108 288 518 116 176 519 19 262 520 19 107 521 31 78 522131 204 523 227 195 524 231 257 525 160 349 526 96 269 527 892 337 528513 198 529 699 55 530 514 44 531 624 110 532 293 69 533 211 53 534 33270 535 871 42 536 203 28 537 670 76 538 685 99 539 452 225 540 339 146541 604 88 542 609 91 543 612 124 544 851 452 545 394 25 546 980 166 547825 322 548 933 295 549 560 190 550 371 63 551 900 867 552 577 385 553302 80 554 739 884 555 887 835 556 246 19 557 994 117 558 684 539 559168 67 372 19 560 476 134 561 388 103 562 803 689 563 985 582 564 817212 565 58 23 566 297 159 567 255 264

The invention claimed is:
 1. A compound of formula (II)

wherein in compounds of the formula (II) ring (A) in the fragment:

represents an aromatic 5- or 6-membered ring or a non-aromatic 5- to7-membered ring, which ring (A) is fused to the phenyl group, whereinsaid ring (A) optionally contains one or two heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; wherein said fragment isoptionally substituted with (R¹)_(n); wherein (R¹)_(n) represents one,two, three, or four optional substituents, wherein said substituents R¹are independently selected from (C₁₋₃)alkyl, (C₂₋₃)alkenyl,(C₂₋₃)alkynyl, (C₁₋₃)alkoxy, halogen, —S—(C₁₋₃)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, cyano, oxo, and —NR^(N7)R^(N8) wherein R^(N7) andR^(N8) independently represent hydrogen or (C₁₋₄)alkyl; R³ representshydrogen, or methyl; Ar¹ represents a phenyl group of the structure(Ar-I):

wherein R^(p) represents (C₄₋₆)cycloalkyl containing a ring oxygen atom,wherein said (C₄₋₆)cycloalkyl containing a ring oxygen atom isunsubstituted or mono-substituted with hydroxy; hydroxy; —X¹—CO—R^(O1),wherein  X¹ represents a direct bond, (C₁₋₃)alkylene,—O—(C₁₋₃)alkylene-*, —NH—(C₁₋₃)alkylene-*, —S—CH₂—* , —CF₂—, —CH═CH—,ethen-1,1-diyl, —C≡C—, —NH—CO—* , —CO—, or (C₃₋₅)cycloalkylene; whereinthe asterisks indicate the bond that is linked to the —CO—R^(O1) group;and  R^(O1) represents  —OH;  —O—(C₁₋₄)alkyl;  —NH—SO₂—R^(S3) whereinR^(S3) represents (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl wherein the(C₃₋₆)cycloalkyl optionally contains a ring oxygen atom,(C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the (C₃₋₆)cycloalkyl optionallycontains a ring oxygen atom, (C₁₋₃)fluoroalkyl, or —NH₂; —O—CH₂—CO—R^(O4), wherein R^(O4) represents hydroxy, or (C₁₋₄)alkoxy,or —N[(C₁₋₄)alkyl]₂;  —O—CH₂—O—CO—R^(O5), wherein R^(O5) represents(C₁₋₄)alkyl or (C₁₋₄)alkoxy;  —O—CH₂—CH₂—N[(C₁₋₄)alkyl]₂; or (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;

2-hydroxy-3,4-dioxo-cyclobut-1-enyl; hydroxy-(C₁₋₄)alkyl;hydroxy-(C₂₋₄)alkoxy; —(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r representsthe integer 0 or 1; and wherein R^(N3) and R^(N4) independentlyrepresent hydrogen, (C₁₋₄)alkyl, hydroxy-(C₂₋₄)alkyl,(C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy; —NR^(N1)R^(N2), wherein R^(N1)independently represents hydrogen or (C₁₋₄)alkyl, and R^(N2)independently represents —CO—H, —CO—(C₁₋₃)alkyl, or—CO—(C₁₋₃)alkylene-OH; —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6)independently represent hydrogen or (C₁₋₄)alkyl; —SO₂—R^(S1) whereinR^(S1) represents (C₁₋₄)alkyl, or —NR^(N7)R^(N8) wherein R^(N7) andR^(N8) independently represent hydrogen or (C₁₋₃)alkyl; —(CH₂)_(q)-HET¹,wherein q represents the integer 0, 1 or 2; and wherein HET¹ represents5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl,3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl, or5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; or —(CH₂)_(p)-HET, wherein prepresents the integer 0 or 1; and wherein HET represents a 5-memberedheteroaryl, wherein said 5-membered heteroaryl is unsubstituted, ormono- or di-substituted, wherein the substituents are independentlyselected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, —COOH, hydroxy,hydroxy-(C₁₋₃)alkyl, (C₃₋₅)cycloalkyl optionally containing one ringoxygen atom, or —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independentlyrepresent hydrogen, (C₁₋₃)alkyl, or hydroxy-(C₂₋₄)alkyl; R^(m1)represents hydrogen; (C₁₋₆)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl;(C₁₋₃)fluoroalkoxy; halogen; (C₃₋₆)cycloalkyl; (C₃₋₆)cycloalkyl-oxy;hydroxy; hydroxy-(C₂₋₄)alkoxy; —X²—NR^(N1)R^(N2), wherein X² representsa direct bond; or X² represents —O—CH₂—CH₂—* , wherein the asteriskindicates the bond that is linked to the —NR^(N1)R^(N2) group; andwherein R^(N1) and R^(N2) independently represent hydrogen, (C₁₋₄)alkyl,or (C₃₋₆)cycloalkyl; or —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl,or (C₃₋₆)cycloalkyl optionally containing one ring oxygen atom; R^(m2)represents hydrogen, methyl, fluoro, or chloro; and R^(o1) representshydrogen; or, in case R^(m2) represents hydrogen, R^(o1) representshydrogen or fluoro; or Ar¹ represents a 5-membered heteroaryl group ofthe structure (Ar-II):

wherein Y represents CR⁸ wherein R⁸ represents hydrogen or halogen; or Yrepresents N; R⁷ represents (C₄₋₆)cycloalkyl containing a ring oxygenatom, wherein said (C₄₋₆)cycloalkyl containing a ring oxygen atom isunsubstituted or mono-substituted with hydroxy; —X¹—CO—R^(O1), wherein X¹ represents a direct bond, (C₁₋₃)alkylene, —O—(C₁₋₃)alkylene-*,—NH—(C₁₋₃)alkylene-*, —S—CH₂—* , —CF₂—, —CH═CH—, —C≡C—, —NH—CO—* , —CO—,or (C₃₋₅)cycloalkylene; wherein the asterisks indicate the bond that islinked to the —CO—R^(O1) group; and  R^(O1) represents  —OH; —O—(C₁₋₄)alkyl;  —NH—SO₂—R^(S3) wherein R^(S3) represents (C₁₋₄)alkyl,(C₃₋₆)cycloalkyl wherein the (C₃₋₆)cycloalkyl optionally contains a ringoxygen atom, (C₃₋₆)cycloalkyl-(C₁₋₃)alkylene wherein the(C₃₋₆)cycloalkyl optionally contains a ring oxygen atom,(C₁₋₃)fluoroalkyl, or —NH₂;  —O—CH₂—CO—R^(O4), wherein R^(O4) representshydroxy, or (C₁₋₄)alkoxy, or —N[(C₁₋₄)alkyl]₂;  —O—CH₂—O—CO—R^(O5),wherein R^(O5) represents (C₁₋₄)alkyl or (C₁₋₄)alkoxy; —O—CH₂—CH₂—N[(C₁₋₄)alkyl]2; or (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;

2-hydroxy-3,4-dioxo-cyclobut-1-enyl; hydroxy-(C₁₋₄)alkyl;hydroxy-(C₂₋₄)alkoxy; —(CH₂)_(r)—CO—NR^(N3)R^(N4) wherein r representsthe integer 0 or 1; and wherein R^(N3) and R^(N4) independentlyrepresent hydrogen, (C₁₋₄)alkyl, hydroxy-(C₂₋₄)alkyl,(C₁₋₃)alkoxy-(C₂₋₄)alkyl, or hydroxy; —NR^(N1)R^(N2), wherein R^(N1)independently represents hydrogen or (C₁₋₄)alkyl, and R^(N2)independently represents —CO—H, —CO—(C₁₋₃)alkyl, or—CO—(C₁₋₃)alkylene-OH; —NH—CO—NR^(N5)R^(N6) wherein R^(N5) and R^(N6)independently represent hydrogen or (C₁₋₄)alkyl; —SO₂—R^(S1) wherein RSIrepresents (C₁₋₄)alkyl, or —NR^(N7)R^(N8) wherein R^(N7) and R^(N8)independently represent hydrogen or (C₁₋₃)alkyl; —(CH₂)_(q)-HET¹,wherein q represents the integer 0, 1 or 2; and wherein HET¹ represents5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl,3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl, or5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; or —(CH₂)_(p)-HET, wherein prepresents the integer 0 or 1; and wherein HET represents a 5-memberedheteroaryl, wherein said 5-membered heteroaryl is unsubstituted, ormono- or di-substituted, wherein the substituents are independentlyselected from (C₁₋₄)alkyl, (C₁₋₄)alkoxy, —COOH, hydroxy,hydroxy-(C₁₋₃)alkyl, (C₃₋₅)cycloalkyl optionally containing one ringoxygen atom, or —NR^(N9)R^(N10) wherein R^(N9) and R^(N10) independentlyrepresent hydrogen, (C₁₋₃)alkyl, or hydroxy-(C₂₋₄)alkyl; R⁶ represents(C₁₋₆)alkyl; (C₁₋₄)alkoxy; (C₁₋₃)fluoroalkyl; (C₁₋₃)fluoroalkoxy;halogen; hydroxy; (C₃₋₆)cycloalkyl; (C₃₋₆)cycloalkyl-oxy;hydroxy-(C₂₋₄)alkoxy; —X²—NR^(N1)R^(N2), wherein X² represents a directbond; or X² represents-O—CH₂—CH₂—* , wherein the asterisk indicates thebond that is linked to the —NR^(N1)R^(N2) group; and wherein R^(N1) andR^(N2) independently represent hydrogen, (C₁₋₄)alkyl, or(C₃₋₆)cycloalkyl; or —S—R^(S2) wherein R^(S2) represents (C₁₋₄)alkyl, or(C₃₋₆)cycloalkyl optionally containing one ring oxygen atom; or Ar¹represents 8- to 10-membered bicyclic heteroaryl; wherein said 8- to10-membered bicyclic heteroaryl independently is mono-substituted with—(C₀₋₃)alkylene-COOR^(O2) wherein R^(O2) represents hydrogen or(C₁₋₄)alkyl; or Ar¹ represents a group of the structure (Ar-III):

which is selected from 2-oxo-2,3-dihydro-benzooxazol-6-yl,3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl,1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl,2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl,1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl,1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1; whereinAr¹ represents a group selected from:

or a pharmaceutically acceptable salt thereof.
 3. The compound accordingto claim 1; wherein Ar¹ represents a group selected from

or a pharmaceutically acceptable salt thereof.
 4. The compound accordingto claim 1; wherein the fragment

represents a group selected from benzofuranyl, benzothiophenyl,benzothiazolyl, benzoisothiazolyl, indolyl, indazolyl, naphthyl,quinolinyl, and isoquinolinyl; which group independently isunsubstituted or substituted with (R¹)_(n); wherein (R¹)_(n) representsone, two, three, or four substituents, wherein said substituents R¹ areindependently selected from (C₁₋₃)alkyl, (C₂₋₃)alkenyl, (C₂₋₃)alkynyl,(C₁₋₃)alkoxy, halogen, —S—(C₁₋₃)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, cyano, or —NR^(N7)R^(N8) wherein R^(N7) and R^(N8)independently represent hydrogen or (C₁₋₄)alkyl; or a group selectedfrom 2,3-dihydro-benzo[b]thiophenyl, benzo[1,3]dioxolyl,1,3-dihydro-isobenzofuranyl, 2,3-dihydro-benzofuranyl, indanyl,5,6,7,8-tetrahydro-naphthalenyl, 2,3-dihydro-benzo[1,4]dioxinyl,chromanyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,1,2,3,4-tetrahydro-quinolinyl, and3,4-dihydro-2H-benzo[b][1,4]dioxepinyl; which group independently isunsubstituted, or substituted with (R¹)_(n); wherein (R¹)_(n) representsone, two, or three substituents, wherein said substituents R¹ areindependently selected from (C₁₋₃)alkyl, (C₂₋₃)alkenyl, (C₂₋₃)alkynyl,(C₁₋₃)alkoxy, halogen, —S—(C₁₋₃)alkyl, (C₁₋₃)fluoroalkyl,(C₁₋₃)fluoroalkoxy, cyano, oxo, or —NR^(N7)R^(N8) wherein R^(N7) andR^(N8) independently represent hydrogen or (C₁₋₄)alkyl; or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 2; wherein the fragment

represents a group selected from the following groups a), b), c), andd), or the following groups e), f) and g): a) benzothiophen-5-yl,benzothiophen-6-yl, 6-methyl-benzothiophen-5-yl,3-methyl-benzothiophen-5-yl, 4-methyl-benzothiophen-5-yl,6-methoxy-benzothiophen-5-yl, 5-methoxy-benzothiophen-6-yl,6-cyano-benzothiophen-5-yl, 3-cyano-benzothiophen-5-yl,6-ethoxy-benzothiophen-5-yl,4-fluoro-7-methoxy-2-methyl-benzothiophen-6-yl, benzoisothiazol-5-yl,benzothiazol-5-yl, benzothiazol-6-yl, benzofuran-5-yl, benzofuran-6-yl,6-fluoro-benzofuran-5-yl, 6-methoxy-benzofuran-5-yl,5-methoxy-benzofuran-6-yl, 2-fluoro-5-methoxy-benzofuran-6-yl,6-methoxy-4-methyl-benzofuran-5-yl,4,5-difluoro-7-methoxy-2-methyl-benzofuran-6-yl, benzooxazol-6-yl,1H-indol-5-yl, 1H-indol-6-yl, 1-methyl-1H-indol-6-yl,1-methyl-1H-indol-5-yl, 6-fluoro-1-methyl-1H-indol-5-yl,1,3-dimethyl-1H-indol-5-yl, 1-ethyl-1H-indol-6-yl, or5-methoxy-1-methyl-1H-indazol-6-yl; b) naphthalen-2-yl,3-chloro-naphthalen-2-yl, 1-chloro-naphthalen-2-yl,8-fluoro-naphthalen-2-yl, 1-fluoro-naphthalen-2-yl,3-methyl-naphthalen-2-yl, 1-methyl-naphthalen-2-yl,1-amino-naphthalen-2-yl, 3-ethynyl-naphthalen-2-yl,1-ethynyl-naphthalen-2-yl, 1-vinyl-naphthalen-2-yl,1,3-difluoro-naphthalen-2-yl, 3-methoxy-naphthalen-2-yl,3-cyano-naphthalen-2-yl, 1-cyano-naphthalen-2-yl,3-methylamino-naphthalen-2-yl, 1-fluoro-3-methoxy-naphthalen-2-yl,4-chloro-3-methoxy-naphthalen-2-yl, 4-fluoro-3-methoxy-naphthalen-2-yl,3-ethoxy-naphthalen-2-yl, 3-methoxy-1-methyl-naphthalen-2-yl,3-cyano-1-fluoro-naphthalen-2-yl, 3-cyano-1-methyl-naphthalen-2-yl,3-isopropoxy-naphthalen-2-yl, or 3-difluoromethoxy-naphthalen-2-yl; c)quinolin-6-yl, 6-fluoro-isoquinolin-7-yl, 7-fluoro-isoquinolin-6-yl,5-fluoro-quinolin-6-yl, 7-methyl-quinolin-6-yl, 8-methyl-quinolin-7-yl,4-chloro-7-methyl-quinolin-6-yl, 7-chloro-8-methyl-quinolin-6-yl,5,8-difluoro-quinolin-6-yl, or 7-chloro-8-fluoro-quinolin-6-yl,5,7-difluoro-quinolin-6-yl; d) 2,3-dihydro-benzo[b]thiophen-5-yl,benzo[1,3]dioxol-5-yl, 6-methoxy-benzo[1,3]dioxol-5-yl,6-cyano-benzo[1,3]dioxol-5-yl,6-chloro-2,2-difluoro-benzo[1,3]dioxol-5-yl,6-difluoromethoxy-benzo[1,3]dioxol-5-yl, 1,3-dihydro-isobenzofuran-5-yl,2,3-dihydro-benzofuran-5-yl, 2,3-dihydro-benzofuran-6-yl, indan-5-yl,3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl,2,3-dihydro-benzo[1,4]dioxin-6-yl,8-chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl,8-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl,8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl, chroman-7-yl, chroman-6-yl,6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl,7-fluoro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl,7-fluoro-1-methyl-1,2,3,4-tetrahydro-quinolin-6-yl,7-methoxy-1,2,3,4-tetrahydro-quinolin-6-yl,7-methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl, or8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl; e)7-methyl-benzothiophen-5-yl, 7-methyl-benzothiophen-6-yl,4-fluoro-benzothiophen-5-yl, 7-fluoro-benzothiophen-5-yl,7-chloro-benzothiophen-5-yl, 3-chloro-benzothiophen-5-yl,3-chloro-7-fluoro-benzothiophen-5-yl,7-fluoro-6-methoxy-benzothiophen-5-yl,7-trifluoromethyl-benzothiophen-5-yl; f)3-ethoxy-1-fluoro-naphthalen-2-yl, 3-ethoxy-1-methyl-naphthalen-2-yl;and g) 7-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl,5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,5-fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl; or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 3; wherein the fragment

represents a group selected from the following groups a), b), c), andd): a) benzothiophen-5-yl, 6-methyl-benzothiophen-5-yl,4-methyl-benzothiophen-5-yl, 6-methoxy-benzothiophen-5-yl,5-methoxy-benzothiophen-6-yl, 3-cyano-benzothiophen-5-yl,6-ethoxy-benzothiophen-5-yl, benzothiazol-5-yl, benzofuran-5-yl,6-fluoro-benzofuran-5-yl, 6-methoxy-benzofuran-5-yl,5-methoxy-benzofuran-6-yl, 6-methoxy-4-methyl-benzofuran-5-yl,1H-indol-5-yl, or 1H-indol-6-yl; b) 1-methyl-naphthalen-2-yl,1-ethynyl-naphthalen-2-yl, 3-methoxy-naphthalen-2-yl,1-fluoro-3-methoxy-naphthalen-2-yl, 3-ethoxy-naphthalen-2-yl,3-methoxy-1-methyl-naphthalen-2-yl, or 3-cyano-1-methyl-naphthalen-2-yl;c) 7-chloro-8-fluoro-quinolin-6-yl, or 5,7-difluoro-quinolin-6-yl; d)2,3-dihydro-benzo[b]thiophen-5-yl, benzo[1,3]dioxol-5-yl,6-methoxy-benzo[1,3]dioxol-5-yl, 6-cyano-benzo[1,3]dioxol-5-yl,6-difluoromethoxy-benzo[1,3]dioxol-5-yl,7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl,7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl, or7-fluoro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl; or apharmaceutically acceptable salt thereof.
 7. A compound selected fromthe group consisting of:3-Ethoxy-5-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-[6-(2-Benzo[b]thiophen-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(5-methoxy-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(2,3-Dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;3-Ethoxy-5-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;2-Cyclobutoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-Ethoxy-5-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid;4-{6-[2-(1-Fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;3-Ethoxy-5-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(8-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-benzofuran-2-carboxylicacid;3-Ethoxy-5-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1-methyl-1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(5,7-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(3-Difluoromethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(3-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-(2-Hydroxy-ethoxy)-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-4-{6-[2-(6-ethoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;5-[6-(2-Chroman-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;3-(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-propionicacid;4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Cyclobutoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;5-{6-[2-(6-Cyano-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(2,3-Dihydro-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;2-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Fluoro-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-6-propyl-benzoicacid;4-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Cyclobutoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(2-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;6-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzofuran-2-carboxylicacid;2-Difluoromethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;6-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-benzofuran-2-carboxylicacid;5-{6-[2-(7-Chloro-8-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-[6-(2-Benzothiazol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzofuran-2-carboxylicacid;5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-2-methyl-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;2-Cyclobutoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(2-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;(2-Ethoxy-4-{6-[2-(3-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;3-Ethoxy-5-{6-[2-(7-fluoro-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;2-Ethoxy-4-{6-[2-(3-ethynyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethylsulfanyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;5-[6-(2-Benzo[1,3]dioxol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;(2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;5-{6-[2-(7-Chloro-8-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;(2-Ethoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;5-{6-[2-(6-Difluoromethoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;(2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;2-Cyclobutoxy-4-{6-[2-(5-methoxy-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-cyclobutoxy-benzoicacid;2-Ethoxy-4-{6-[2-(6-ethoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-1H-indole-4-carboxylicacid;4-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoicacid;4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid;5-[6-(2-Benzo[d]isothiazol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;4-{6-[2-(2,3-Dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;5-[6-(2-Benzooxazol-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-aceticacid;2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(5-Methoxy-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-benzoicacid;(2-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;2-Ethylsulfanyl-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(2-Ethoxy-4-{6-[2-(5-methoxy-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;(2-Ethoxy-4-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;5-{6-[2-(1,3-Dihydro-isobenzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;2-Butoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(2,3-dihydro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(3-ethoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;5-{6-[2-(4-Chloro-7-methyl-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(1-Methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-benzoicacid;(2-Ethoxy-4-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;3-(3-Ethoxy-5-{6-[2-(1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(5-(6-((2-(1H-indol-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol;3-{5-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one;3-(5-(6-((2-(Benzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol;3-(3-Ethoxy-5-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(7-methyl-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol;3-(3-Ethoxy-5-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(6-methoxybenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol;3-(3-Ethoxy-5-{6-[2-(1H-indol-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(5-(6-((2-(1H-indol-6-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol;3-{5-[6-(2-Benzo[1,3]dioxol-5-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one;3-(5-(6-((2-(Benzo[d][1,3]dioxol-5-yl)ethyl)amino)pyrimidin-4-yl)-3-ethoxythiophen-2-yl)-[1,2,4]oxadiazol-5-ol;3-(3-Ethoxy-5-{6-[2-(7-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(7-fluoroquinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol;{6-[4-Ethoxy-5-(1H-tetrazol-5-yl)-thiophen-2-yl]-pyrimidin-4-yl}-[2-(7-fluoro-quinolin-6-yl)-ethyl]-amine;4-Ethoxy-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazole-5-carboxylicacid;3-(4-Ethoxy-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(4-Ethoxy-2-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol;3-(4-Ethyl-2-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiazol-5-yl)-[1,2,4]oxadiazol-5(4H)-one;3-(4-Ethyl-2-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiazol-5-yl)-[1,2,4]oxadiazol-5-ol;3-Ethoxy-5-(6-((2-(1-methylnaphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)-N-sulfamoylthiophene-2-carboxamide;N-(3-Ethoxy-5-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carbonyl)-methanesulfonamide;2-Cyclobutoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(6-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;4-{6-[2-(6-Methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Cyclobutoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;6-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzofuran-3-carboxylicacid;4-{6-[2-(4-Methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Cyclobutoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(3-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Cyclobutoxy-4-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(6-methoxy-4-methyl-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-phenyl)-aceticacid;2-Ethoxy-4-{6-[2-(6-fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-(2-Ethoxy-4-{6-[2-(6-methoxy-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionicacid;4-{6-[2-(6-Fluoro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;4-[6-(2-Benzofuran-5-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid;4-[6-(2-Benzofuran-6-yl-ethylamino)-pyrimidin-4-yl]-2-methylsulfanyl-benzoicacid;2-Ethoxy-4-{6-[2-(6-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(6-Methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Ethoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(7-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(6-methoxy-benzo[1,3]dioxol-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-Ethoxy-5-{6-[2-(1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-fluoro-1-methyl-1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(4-Chloro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(8-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(8-methyl-quinolin-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;5-{6-[2-(1-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-[6-(2-naphthalen-2-yl-ethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylicacid;(2-Ethoxy-4-{6-[2-(1-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;3-Ethoxy-5-{6-[2-(3-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-[6-(2-indan-5-yl-ethylamino)-pyrimidin-4-yl]-thiophene-2-carboxylicacid;5-{6-[2-(8-Chloro-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoicacid;5-{6-[2-(4,5-Difluoro-7-methoxy-2-methyl-benzofuran-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-[6-(2-Chroman-7-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(3-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;(2-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;5-{6-[2-(3-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(1-methyl-1H-indol-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(8-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(5-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;2-Cyclobutoxy-4-{6-[2-(7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;5-{6-[2-(1-Amino-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-{6-[2-(7-Fluoro-1-methyl-1,2,3,4-tetrahydro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid;4-{6-[2-(3-Cyano-1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoicacid;3-Ethoxy-5-{6-[2-(1-vinyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;2-Isobutyl-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-Ethoxy-5-{6-[2-(7-methylsulfanyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;(4-{6-[2-(6-Cyano-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-aceticacid;(4-{6-[2-(3-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenoxy)-aceticacid;5-{6-[2-(5,8-Difluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;(2-Ethoxy-4-{6-[2-(3-isopropoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;5-{6-[2-(1-Chloro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;5-[6-(2-Benzothiazol-6-yl-ethylamino)-pyrimidin-4-yl]-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(3-Cyano-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoicacid;3-Ethoxy-5-{6-[2-(4-fluoro-7-methoxy-2-methyl-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(7-fluoro-quinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-Ethoxy-5-{6-[2-(6-fluoro-isoquinolin-7-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;(4-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-aceticacid;5-{6-[2-(7-Fluoro-isoquinolin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-trifluoromethyl-thiophene-2-carboxylicacid;4-{6-[2-(7-Cyano-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxy-benzoicacid;5-{6-[2-(2,3-Dihydro-benzofuran-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;(4-{6-[2-(1-Fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-phenyl)-aceticacid;{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-ethoxy-phenoxy}-aceticacid;(2-Ethoxy-4-{6-[2-(3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-aceticacid;2-Ethoxy-4-{6-[2-(4-fluoro-3-methoxy-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;5-{6-[2-(1,3-Difluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;3-{3-Ethoxy-5-[6-(2-quinolin-6-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one;3-(3-Ethoxy-5-(6-((2-(quinolin-6-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol;3-{3-Ethoxy-5-[6-(2-naphthalen-2-yl-ethylamino)-pyrimidin-4-yl]-thiophen-2-yl}-[1,2,4]oxadiazol-5(4H)-one;and3-(3-Ethoxy-5-(6-((2-(naphthalen-2-yl)ethyl)amino)pyrimidin-4-yl)thiophen-2-yl)-[1,2,4]oxadiazol-5-ol;or a pharmaceutically acceptable salt thereof.
 8. A compound selectedfrom the group consisting of:5-{6-[2-(7-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;4-{6-[2-(7-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;2-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-Ethoxy-5-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-6-fluoro-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethoxy-6-fluoro-4-{6-[2-(4-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;3-Ethoxy-5-{6-[2-(7-methyl-benzo[b]thiophen-6-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid;4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid;4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid;4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid;(2-Methoxy-4-{6-[2-(6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-aceticacid;(2-Methoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Methoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid;3-Ethoxy-5-{6-[2-(7-methyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-phenyl)-aceticacid;(4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-phenyl)-aceticacid;2-Ethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(4-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(2-Ethoxy-6-fluoro-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;4-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(2-Ethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-6-fluoro-phenyl)-aceticacid;2-Ethoxy-4-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-4-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;2-Cyclobutoxy-4-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(4-{6-[2-(5-Fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-phenyl)-aceticacid;(2-Isobutyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-phenyl)-aceticacid;4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoicacid;4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoicacid;4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoicacid;2-Ethoxy-4-{6-[2-(3-ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(3-Ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(2-Ethoxy-4-{6-[2-(3-ethoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;3-(2-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionicacid;3-(2-Ethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionicacid;(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropoxy-phenyl)-aceticacid;(2-Isopropoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-aceticacid;(4-{6-[2-(7-Methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-aceticacid;4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-cyclobutoxy-benzoicacid;(4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-aceticacid;2-Isopropoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;5-{6-[2-(7-Difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-3-ethoxy-thiophene-2-carboxylicacid;(2-Methoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;2-Ethoxy-4-{6-[2-(5-fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(3-ethoxy-1-fluoro-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenoxy)-propionicacid;2-Ethoxy-4-{6-[2-(7-ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(4-{6-[2-(7-Ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(2-Difluoromethoxy-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Difluoromethoxy-4-{6-[2-(5-fluoro-7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Difluoromethoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethyl-4-{6-[2-(7-methoxy-5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethyl-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;2-Ethyl-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclopropoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclopropoxy-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclopropoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(4-{6-[2-(7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-aceticacid;3-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5(4H)-one;3-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5-ol;{6-[3-Ethoxy-4-(1H-tetrazol-5-yl)-phenyl]-pyrimidin-4-yl}-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethyl]-amine;4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutoxy-benzoicacid;(3-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-aceticacid;4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzamide;4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-benzoicacid;3-Ethoxy-5-{6-[2-(7-fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;(4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-aceticacid;(4-{6-[2-(7-Fluoro-6-methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;2-(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-propionicacid;4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-benzoicacid;4-{6-[2-(7-Difluoromethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methylsulfanyl-benzoicacid;(4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(4-{6-[2-(3-Chloro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-aceticacid;(4-{6-[2-(3-Methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-aceticacid;(4-{6-[2-(7-Ethynyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-aceticacid;(4-{6-[2-(5-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(2-Difluoromethoxy-4-{6-[2-(7-ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;2-Ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclopropoxy-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclopropoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(3-Difluoromethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-aceticacid;3-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazole-5(4H)-thione;3-(2-Ethoxy-4-{6-[2-(1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazole-5-thiol;(4-{6-[2-(6-Methoxy-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propoxy-phenyl)-aceticacid;2-Butoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Ethoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(4-{6-[2-(5-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-trifluoromethoxy-phenyl)-aceticacid;(4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethyl-phenyl)-aceticacid;2-Ethyl-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;4-{6-[2-(7-Ethoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-ethyl-benzoicacid;2-Cyclopropoxy-4-{6-[2-(5-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;(4-{6-[2-(7-Methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(4-{6-[2-(3-Cyano-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-2-ethoxy-phenyl)-aceticacid;(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethoxy-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethoxy-6-fluoro-4-{6-[2-(3-methoxy-1-methyl-naphthalen-2-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethoxy-6-fluoro-4-{6-[2-(4-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-aceticacid;(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-phenyl)-aceticacid;4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isobutyl-benzoicacid;2-Isobutyl-4-{6-[2-(7-methoxy-2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-propionicacid;(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-isopropoxy-phenyl)-aceticacid;3-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenoxy)-propionicacid;3-Ethyl-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-N-(2-hydroxy-ethyl)-benzamide;(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-aceticacid;2-{4-[6-(2-Benzo[b]thiophen-5-yl-ethylamino)-pyrimidin-4-yl]-2-propyl-phenyl}-propionicacid;2-(4-{6-[2-(4-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-propyl-phenyl)-propionicacid;3-Ethoxy-5-{6-[2-(7-trifluoromethyl-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophene-2-carboxylicacid;3-(4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)phenyl)-[1,2,4]oxadiazol-5(4H)-one;3-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-[1,2,4]oxadiazol-5-ol;7-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-1-methyl-3,4-dihydro-1H-quinazolin-2-one;4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2,6-dimethyl-phenol;2-Ethylsulfanyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;2-Cyclobutoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid;3-(3-Ethoxy-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-propionicacid;3-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-4-hydroxy-cyclobut-3-ene-1,2-dione;(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-oxo-aceticacid;2-Cyclopropoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-benzoicacid methyl ester;(2-Chloro-6-ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-aceticacid;(2-Ethyl-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-6-methyl-phenyl)-aceticacid;(3-Ethyl-5-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-thiophen-2-yl)-aceticacid;5-(2-Ethoxy-4-{6-[2-(7-fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-phenyl)-isoxazol-3-ol;5-(2-ethoxy-4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)phenyl)isoxazol-3(2H)-one;5-(4-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-2-methoxy-phenyl)-isoxazol-3-ol;5-(4-(6-((2-(7-fluorobenzo[b]thiophen-5-yl)ethyl)amino)pyrimidin-4-yl)-2-methoxyphenyl)isoxazol-3(2H)-one;and(5-{6-[2-(7-Fluoro-benzo[b]thiophen-5-yl)-ethylamino]-pyrimidin-4-yl}-3-propyl-thiophen-2-yl)-aceticacid; or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising, as active principle, a compound according claim1, or a pharmaceutically acceptable salt thereof, and at least onetherapeutically inert excipient.
 10. A method of modulating an immuneresponse in a subject having a tumor, comprising administering to asubject in need thereof an effective amount of a compound of formula(II) according to claim 1, or a pharmaceutically acceptable saltthereof, wherein said effective amount reactivates the subject's immunesystem in the tumor.
 11. A method of treatment of cancer; pain;endometriosis; autosomal dominant polycystic kidney disease; an acuteischemic syndrome in an atherosclerotic patient; pneumonia; or aneurodegenerative disease; or for control of female fertility;comprising administering to a subject in need thereof an effectiveamount of a compound of formula (II) according to claim 1, or apharmaceutically acceptable salt thereof.
 12. A method of treatment of acancer selected from melanoma; lung cancer; bladder cancer; renalcarcinomas; gastro-intestinal cancers; endometrial cancer; ovariancancer; cervical cancer; neuroblastoma; and prostate cancer; comprisingadministering to a subject in need thereof an effective amount of acompound of formula (II) according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 13. A method of treatment of a cancer in asubject in need thereof, wherein said cancer is treated by modulating animmune response comprising a reactivation of subject's immune system intumor; comprising administering to the subject an effective amount of acompound of formula (II) according to claim 1, or a pharmaceuticallyacceptable salt thereof, and optionally administering one or morechemotherapy agents and/or radiotherapy and/or targeted therapy.
 14. Apharmaceutical composition comprising, as active principle, a compoundaccording claim 7, or a pharmaceutically acceptable salt thereof, and atleast one therapeutically inert excipient.
 15. A method of treatment ofcancer; pain; endometriosis; autosomal dominant polycystic kidneydisease; an acute ischemic syndrome in an atherosclerotic patient;pneumonia; or a neurodegenerative disease; or for control of femalefertility; comprising administering to a subject in need thereof aneffective amount of a compound according to claim 7, or apharmaceutically acceptable salt thereof.
 16. A method of treatment of acancer in a subject in need thereof, wherein said cancer is treated bymodulating an immune response comprising a reactivation of subject'simmune system in tumor; comprising administering to the subject aneffective amount of a compound according to claim 7, or apharmaceutically acceptable salt thereof, and optionally administeringone or more chemotherapy agents and/or radiotherapy and/or targetedtherapy.
 17. A pharmaceutical composition comprising, as activeprinciple, a compound according claim 8, or a pharmaceuticallyacceptable salt thereof, and at least one therapeutically inertexcipient.
 18. A method of treatment of a cancer selected from melanoma;lung cancer; bladder cancer; renal carcinomas; gastro-intestinalcancers; endometrial cancer; ovarian cancer; cervical cancer;neuroblastoma; and prostate cancer; comprising administering to asubject in need thereof an effective amount of a compound according toclaim 8, or a pharmaceutically acceptable salt thereof.
 19. A method oftreatment of cancer; pain; endometriosis; autosomal dominant polycystickidney disease; an acute ischemic syndrome in an atheroscleroticpatient; pneumonia; or a neurodegenerative disease; or for control offemale fertility; comprising administering to a subject in need thereofan effective amount of a compound according to claim 8, or apharmaceutically acceptable salt thereof.
 20. A method of treatment of acancer in a subject in need thereof, wherein said cancer is treated bymodulating an immune response comprising a reactivation of subject'simmune system in tumor; comprising administering to the subject aneffective amount of a compound according to claim 8, or apharmaceutically acceptable salt thereof, and optionally administeringone or more chemotherapy agents and/or radiotherapy and/or targetedtherapy.